Morpholino and oxazoline substituted carbostyril derivatives, process for producing the same and cardiotonic compositions containing the same

ABSTRACT

Novel carbostyril derivatives and their pharmaceutically acceptable salts represented by the formula (1). ##STR1## wherein R 1  is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group, R 2  and R 3  form, together with the adjacent nitrogen atom and further with an additional oxygen atom, a 5- or 6-membered saturated heterocyclic ring which may have a lower alkyl group or a phenyl-lower alkyl group as the substituent; the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton being a single or double bond. The derivatives are useful as the active ingredient in cardiotonic compositions.

This is a division of application Ser. No. 348,709, filed Feb. 16, 1982.

The present invention relates to novel carbostyril derivatives and theirsalts, processes for producing the same and cardiotonic compositionscontaining the same as the active ingredients.

Carbostyril derivatives and their salts of the present invention arerepresented by the following general formula (1). ##STR2## wherein R¹ isa hydrogen atom, a lower alkyl group, a lower alkenyl group, a loweralkynyl group or a phenyl-lower alkyl group; R² and R³ may be the sameor different and each are a lower alkyl group which may have hydroxygroup(s) or halogen atom(s) as the substituent(s), or a phenyl-loweralkyl group which may have 1 to 3 substituents selected from the groupconsisting of a lower alkoxy group and a halogen atom on the phenylring, or said phenyl-lower alkyl group may have a lower alkylenedioxygroup as the substituent on the phenyl ring; further R² and R³ may form,together with the adjacent nitrogen atom and further with or without anadditional oxygen or nitrogen atom, a 5- or 6-membered saturatedheterocyclic ring which may have a lower alkyl group or a phenyl-loweralkyl group as the substituent; when said heterocyclic ring is apiperazinyl group, the piperazinyl ring may have a lower alkyl group ora phenyl-lower alkyl group as the substituent at 4-position in thepiperazinyl ring, further said piperazinyl group may have, as thesubstituent at 4-position, a lower alkenyl group, a lower alkynyl group,a cycloalkyl group, a cycloalkyl-lower alkyl group, a lower alkanoylgroup, a lower alkanoyl-lower alkyl group, a lower alkoxycarbonyl group,a lower alkoxycarbonyl-lower alkyl group, a furoyl group, a loweralkylsulfonyl group, a substituted lower alkyl group (having onesubstituent selected from the group consisting of a cyano group, abenzoyloxy group (which may have 1 to 3 lower alkoxy groups on thephenyl ring), a hydroxy group, a lower alkanoyloxy group, a halogen atomand a carbamoyl group), a phenoxy-lower alkyl group (which may have, onthe phenyl ring, 1 to 3 substituents selected from the group consistingof a halogen atom, a lower alkoxy group and a lower alkyl group, or saidphenoxy-lower alkyl group may have, on the phenyl ring, a loweralkylenedioxy group as the substituent), a phenyl-lower alkyl group(which may have, on the phenyl ring, 1 to 3 substituents selected fromthe group consisting of lower alkyl group, a lower alkoxy group, ahalogen atom, a nitro group, an amino group, a lower alkanoylamino groupand a lower alkylthio group, or said phenyl-lower alkyl group may have,on the phenyl ring, a lower alkylenedioxy group as the substituent), abenzoyl group (which may have, on the phenyl ring, 1 to 3 substituentsselected from the group consisting of a lower alkyl group, a loweralkoxy group, a halogen atom, a nitro group and a cyano group, or saidbenzoyl group may have, on the phenyl ring, a lower alkylenedioxy groupas the substituent), a phenylsulfonyl group (which may have, on thephenyl ring, 1 to 3 lower alkyl groups as the substituents), abenzoyl-lower alkyl group (which may have, on the phenyl ring, 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxy group, a lower alkyl group, a lower alkoxy group and a loweralkanoylamino group), a phenyl-lower alkenylcarbonyl group (which mayhave, on the phenyl ring, 1 to 3 substituents selected from the groupconsisting of a halogen atom, and a lower alkoxy group), or aphenyl-lower alkanoyl group (which may have, on the pheny ring, 1 to 3lower alkoxy groups as the substituents); the carbon-carbon bond between3- and 4-positions in the carbostyril skeleton is a single or doublebond.

Carbostyril derivatives of the present invention represented by thegeneral formula (1) have myocardial contraction increasing activity(positive inotropic activity), coronary blood flow increasing activityand hypotensive activity, and thus they are useful as cardiotonics forcuring various heat diseases such as congestive heart failure, mitralvalvular disease, atrial fibrillation and flutter and paroxysmal artrialtachycardia.

Specifically, carbostyril derivatives of the present inventionrepresented by the general formula (1) have excellent properties inpositive inotropic activity, coronary blood flow increasing activity andhypotensive activity, while they have almost no heart beat increasingactivity.

Some carbostyril derivatives having useful pharmacological activities,such as bronchiectactic agent, antihistaminic agent, anti-hypertensiveagent and central nervous system controlling agent are known in priorart literatures, for example:

(a) Japanese Patent Application Kokai (Laid-open) No. 12515/1978discloses carbostyril derivatives having side-chain of the formula,##STR3## (wherein R¹ and R² may form, together with the adjacentnitrogen atom, a substituted or unsubstituted heterocyclic ring), on thecontrary the carbostyril derivatives represented by the general formula(1) of the present invention having the side chain of the formula##STR4## thus the carbonyl group --CO-- is connected to the group of theformula ##STR5## directly, without connected through a methylene groupof the formula --CH₂ --. The carbostyril derivatives disclosed in thisliterature (a) are useful as intermediate compounds for preparingpharmaceutical chemicals such as telangietatic agents, hypotensiveagents and the like. In this connection, the inventors believe that thepharmacological activities of compounds having side-chain of whichchemical structural formulas are different from those of the carbostyrilderivatives represented by the general formula (1) of the presentinvention should be different from the latter.

(b) Japanese Patent Application Kokai (Laid-open) No. 118771/1976discloses carbostyril derivatives having side-chain of the formula##STR6## thus similar to the side-chain as explained in the literature(a) above, the carbonyl group --CO-- is connected to the group of theformula ##STR7## through group of the formula ##STR8## Also thepharmacological activities of carbostyril derivatives disclosed in thisliterature (b) are different from those of carbostyril derivativerepresented by the general formula (1) of the present invention. Thecarbostyril derivatives of this literature (b) are useful asintermediate compounds for preparing pharmaceutical chemicals such astelangietatic agent an the like.

(c) Japanese Patent Application Kokai (Laid-open) No. 16478/1979discloses carbostyril derivatives having side-chain wherein the carbonylgroup --CO-- and the group of the formula ##STR9## are connected througha group of the formula ##STR10## and the pharmacological activitiesthereof are also different from those of carbostyril derivativesrepresented by the general formula (1) of the present invention.Carbostyril derivative disclosed in this literature (c) are useful asbronchietatic agent, antihistaminic agent and anti-hypertensive agent.

(d) Belgian Pat. No. 887800 and

(e) British Patent Application (Laid-open) No. 2071-094 disclosecarbostyril derivatives having side-chain wherein the carbonyl group--C-- and a group of the formula ##STR11## are connected to each otherthrough a lower alkyl group. The pharmacological activities ofcarbostyril derivatives disclosed in these literatures are differentfrom those of the carbostyril derivatives represented by the generalformula (1) of the present invention. The carbostyril derivativesdisclosed in these literatures are useful as central nervous systemcontrolling agent and antihistaminic agent.

(f) Japanese Patent Application Kokai (Laid-open) No. 16470/1981discloses carbostyril derivatives having side-chain of the formula--O--D--SO_(m) --R² which is essentially different from the side-chainof the formula ##STR12## being contained in the carbostyril derivativesrepresented by the general formula (1) of the present invention.

The carbostyril derivatives disclosed in this literature (f) indeed havepositive inotropic activity (myocardial contraction increasing activity)and antithrombotic activity, thus one of the pharmacological activitiesthereof (myocardial increasing activity) is similar to thepharmacological activity being shown by carbostyril derivativesrepresented by the general formula (1) of the present invention, buttype of the side chain contained in the former carbostyril derivativesis different from that contained in the latter carbostyril derivatives.

Next, concrete examples of the groups as defined in the symbols R¹, R²and R³ in the general formula (1) are exemplified as follows:

The expression "a lower alkyl group" means a straight chain or branchedchain alkyl group having 1 to 6 carbon atoms and the examples includingmethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexylgroups and the like.

The expression "a lower alkenyl group" means a straight chain orbranched chain alkenyl group having 2 to 6 carbon atoms, and theexamples including vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl,2-pentenyl and 2-hexenyl groups and the like.

The expression "a lower alkynyl group" means a straight chain orbranched chain alkynyl group having 2 to 6 carbon atoms, and theexamples including ethynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl,2-pentynyl and 2-hexynyl groups and the like.

The expression "a phenyl-lower alkyl group" means a phenylalkyl group inwhich the alkyl group is a straight chain or branched chain alkyl grouphaving 1 to 6 carbon atoms, and the examples including benzyl,2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl and2-methyl-3-phenylpropyl groups and the like.

The expression "cycloalkyl-lower alkyl group" means a straight chain orbranched chain alkyl group having 1 to 6 carbon atoms to which acycloalkyl group having 3 to 8 carbon atoms is attached, and theexamples including cyclopropylmethyl, 4-cyclohexylbutyl,2-cyclopentylethyl, cyclohexylmethyl, 2-cyclopentylpropyl,3-cyclohexylpropyl, cyclopentylmethyl, 2-cyclohexylethyl,2-cyclohexylpropyl, 2-cycloheptylethyl, 3-cyclobutylpropyl,1,1-dimethyl-2-cyclohexylethyl, 1-methyl-2-cyclopentylethyl,2-cyclooctylethyl, 5-cyclohexylpentyl, and 6-cyclohexylhexyl groups andthe like.

The expression "a lower alkanoyl group" means a straight chain orbranched chain alkanoyl group having 1 to 6 carbon atoms in the alkylmoiety, and the examples including formyl, acetyl, propionyl, butyryl,isobutryl, pentanoyl, tertbutylcarbonyl and hexanoyl groups and thelike.

The expression "a lower alkoxycarbonyl group" means a straight chain orbranched chain alkoxycarbonyl group in which the alkoxy group having 1to 6 carbon atoms, and the examples including methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups andthe like.

The expression "a lower alkylsulfonyl group" means a straight chain orbranched chain alkylsulfonyl group having 1 to 6 carbon atoms, and theexamples including methanesulfonyl, ethanesulfonyl, propanesulfonyl,isopropanesulfonyl, butanesulfonyl, tert-butanesulfonyl andpentanesulfonyl and hexanesulfonyl groups and the like.

The expression "a phenoxy-lower alkyl group (which may have, on thephenyl ring, 1 to 3 substituents selected from the group consisting of ahalogen atom, a lower alkoxy group and a lower alkyl group, or saidphenoxy-lower alkyl group may have, on the phenyl ring, a loweralkylenedioxy group as the substituent)" means a straight chain orbranched chain alkyl group having 1 to 6 carbon atoms to which a phenoxygroup is attached, said phenoxy group may have, on the phenyl ring, 1 to3 substituents selected from the group consisting of a halogen atom, analkoxy group having 1 to 6 carbon atoms and an alkyl group having 1 to 6carbon atoms, or said phenoxy group may have, on the phenyl ring, analkylenedioxy group having 1 to 4 carbon atoms as the substituent, andthe examples including phenoxymethyl, 2-phenoxyethyl, 2-phenoxypropyl,3-phenoxypropyl, 1-methyl-2-phenoxyethyl, 2-phenoxybutyl,3-phenoxybutyl, 4-phenoxybutyl, 1,1-dimethyl-2-phenoxybutyl,2-phenoxypentyl, 3-phenoxypentyl, 4-phenoxyhexyl,(2-methoxyphenoxy)methyl, (3-methoxyphenoxy)methyl,2-(4-methoxyphenoxy)ethyl, (2-ethoxyphenoxy)methyl,1-(3-ethoxyphenoxy)ethyl, 3-(4-ethoxyphenoxy)propyl,6-(4-isopropoxyphenoxy)hexyl, 4-(4-hexyloxyphenoxy)butyl,1,1-dimethyl-2-(3,4-dimethoxyphenoxy)ethyl,5-(3,4-diethoxyphenoxy)pentyl, 6-(3,4,5-trimethoxyphenoxy)hexyl,2-methyl-3-(2,5-dimethoxyphenoxy)propyl, (2-chlorophenoxy)methyl,(3-bromophenoxy)-methyl, (4-iodophenoxy)methyl,2-(4-fluorophenoxy)ethyl, 1-(3-chlorophenoxy)ethyl,6-(4-bromophenoxy)hexyl, 5-(3,4-dichlorophenoxy)pentyl,1,1-dimethyl-2-(2,5-dibromophenoxy)propyl,(3,4,5-trichlorophenoxy)methyl, (2-ethylphenoxy)methyl,(3-methylphenoxy)methyl, 2-(4-methylphenoxy)ethyl,(2-ethylphenoxy)methyl, 1-(3-ethylphenoxy)ethyl,3-(4-ethylphenoxy)propyl, 6-(4-isopropylphenoxy)hexyl,4-(4-hexylphenoxy)butyl, 1,1-dimethyl-2-(3,4-dimethylphenoxy)ethyl,5-(3,4-diethylphenoxy)pentyl, 6-(3,5-dimethylphenoxy)hexyl,2-methyl-3-(2,5-dimethylphenoxy)propyl,(3,4-methylenedioxyphenoxy)methyl, 2-(3,4-methylenedioxyphenoxy)ethyl,2-(3,4-ethylenedioxyphenoxy)ethyl, 2-(2,3-methylenedioxyphenoxy)ethyl,2-( 3,4-trimethylenedioxyphenoxy)ethyl,4-(3,4-methylenedioxyphenoxy)butyl, (3,4-ethylenedioxyphenoxy)methyl,(2,3-methylenedioxyphenoxy)methyl, 1-(3,4-methylenedioxyphenoxy)ethyl,3-(3,4-methylenedioxyphenoxy)propyl, 6-(3,4-methylenedioxyphenoxy)hexyl,(3,4,5-trimethylphenoxy)methyl, (3,4,5-trimethoxyphenoxy)-methyl and2-(3,4,5-trimethoxyphenoxy)ethyl groups and the like.

The expression "a substituted lower alkyl group (having one substituentselected from the group consisting of a cyano group, a benzoyloxy group(which may have 1 to 3 lower alkoxy groups, as the substituents, on thephenyl ring), a hydroxy group, a lower alkanoyloxy group, a halogen atomand a carbamoyl group)" means a straight chain or branched chain alkylgroup having 1 to 6 carbon atoms, containing one substituent selectedfrom the group consisting of a cyano group, a benzoyloxy group (whichmay have 1 to 3 straight chain or branched chain alkoxy groups on thephenyl ring), a hydroxy group, a straight chain or branched chainalkanoyloxy group having 1 to 6 carbon atoms in the alkyl moiety, ahalogen atom and a carbamoyl group, and the examples includingcyanomethyl, carbamoylmethyl, 2-cyanoethyl, 2-carbamoylethyl,2-cyanopropyl, 3-cyanopropyl, 2-carbamoylpropyl, 3-carbamoylpropyl,1-methyl-2-cyanoethyl, 1-methyl-2-carbamoylethyl, 2-cyanobutyl,3-cyanobutyl, 4-cyanobutyl, 2-carbamoylbutyl, 3-carbamoylbutyl,4-carbamoylbutyl, 1,1 -dimethyl-2-cyanobutyl,1,1-dimethyl-2-carbamoylbutyl, 2-cyanopentyl, 3-cyanopentyl,2-carbamoylpentyl, 3-carbamoylpentyl, 4-cyanohexyl, 4-carbamoylhexyl,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxybutyl,3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl,6-hydroxyhexyl, acetyloxymethyl, 2-acetyloxyethyl, 2-acetyloxypropyl,3-acetyloxypropyl, 4-acetyloxybutyl, 3-acetyloxybutyl,5-acetyloxypentyl, 6-acetyloxyhexyl, 2-propionyloxyethyl,3-formyloxypropyl, 2-butyryloxypropyl, 4-isobutyryloxybutyl,2-pentanoyloxyethyl, tert-butylcarbonyloxymethyl, 2-hexanoyloxyethyl,benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl,6-benzoyloxyhexyl, 4-benzoyloxybutyl, 2-methoxybenzoyloxymethyl,3-methoxybenzoyloxymethyl, 2-(4-methoxybenzoyloxy)ethyl,2-ethoxybenzoyloxymethyl, 1-(3-ethoxybenzoyloxy)ethyl,3-(4-ethoxybenzoyloxy)propyl, 6-(4-isopropoxybenzoyloxy)hexyl,4-(4-hexyloxybenzoyloxy)-butyl,1,1-dimethyl-2-(3,4-dimethylbenzoyloxy)ethyl, 5-benzoyloxypentyl,5-(3,4-diethoxybenzoyloxy)pentyl, 6-(3,4,5-trimethoxybenzoyloxy)hexyl,2-methyl-3-(2,5-dimethoxybenzoyloxy)propyl,2-(3,4-dimethoxybenzoyloxy)-ethyl, 3-(3,4,5-trimethoxybenzoyloxy)propyl,chloromethyl, bromomethyl, iodomethyl, fluoromethyl, 2-chloroethyl,2-bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-fluoropropyl,3-iodopropyl, 1-methyl-2-chloroethyl, 2-bromobutyl, 3-bromobutyl,4-bromobutyl, 3-chlorobutyl, 2-iodobutyl, 4-fluorobutyl,1,1-dimethyl-2-chlorobutyl, 2-chloropentyl, 3-chloropentyl,4-bromohexyl, 6-chlorohexyl and 5-bromopentyl groups and the like.

The expression "a phenyl-lower alkyl group (which may have, on thephenyl ring, 1 to 3 substituents selected from the group consisting of alower alkyl group, a lower alkoxy group, a halogen atom, a nitro group,an amino group, a lower alkanoylamino group and a lower alkylthio group,or said phenyl-lower alkyl group may have, on the phenyl ring, a loweralkylenedioxy group as the substituent)" means a straight chain orbranched chain alkyl group having 1 to 6 carbon atoms, to which one ortwo phenyl groups are attached, said phenyl groups may respectivelyhave, 1 to 3 substituents selected from the group consisting of astraight chain or branched chain alkyl group having 1 to 6 carbon atoms,a straight chain or branched chain alkoxy group having 1 to 6 carbonatoms, a halogen atom, a nitro group, an amino group, a straight chainor branched chain alkanoylamino group having 1 to 6 carbon atoms in thealkyl moiety, and a straight chain or branched chain alkylthio grouphaving 1 to 6 carbon atoms, or said phenyl-alkyl group may have, on thephenyl ring, an alkylenedioxy group having 1 to 4 carbon atoms as thesubstituent, and the examples including benzyl, 2-phenylethyl,3-phenylpropyl, 6-phenylhexyl, 4 -phenylbutyl, diphenylmethyl,1,2-diphenylethyl, 2-methoxybenzyl, 3-methoxybenzyl,2-(4-methoxyphenyl)-ethyl, 2-ethoxybenzyl, 1-(3-ethoxyphenyl)ethyl,3-(4-ethoxyphenyl)propyl, 6-(4-isopropoxyphenyl)hexyl,4-(4-hexyloxyphenyl)butyl, 1,1-dimethyl-2-(3,4-dimethoxyphenyl)ethyl,5-phenylpentyl, 5-(3,4-diethoxyphenyl)pentyl,6-(3,4,5-trimethoxyphenyl)hexyl, 2-methyl-3-(2,5-dimethoxyphenyl)propyl,2-nitrobenzyl, 3-nitrobenzyl, 1-(3-nitrophenyl)ethyl,6-(4-nitrophenyl)hexyl, 2-chlorobenzyl, 3-bromobenzyl, 4-iodobenzyl,2-(4-fluorophenyl)-ethyl, 1-(3-chlorophenyl)ethyl,6-(4-bromophenyl)hexyl, 5-(3,4-dichlorophenyl)pentyl,1,1-dimethyl-2-(2,5-dibromophenyl)propyl, 2-methylbenzyl,3-methylbenzyl, 2-(4-methylphenyl)ethyl, 2-ethylbenzyl,1-(3-ethylphenyl)-ethyl, 3-(4-ethylphenyl)propyl,6-(4-isopropylphenyl)-hexyl, 4-(4-hexylphenyl)butyl,1,1-dimethyl-2-(3,4-dimethylphenyl)ethyl, 5-(3,4-diethylphenyl)pentyl,6-(3,5-dimethylphenyl)hexyl, 2-methyl-3-(2,5-dimethylphenyl)propyl,2-aminobenzyl, 3-aminobenzyl, 1-(3-aminophenyl)ethyl,6-(4-aminophenyl)hexyl, 2-acetylaminobenzyl, 3-formylaminobenzyl,1-(3-propionylaminophenyl)ethyl, 6-(4-n-butyrylaminophenyl)hexyl,2-(5-pentanoylaminophenyl)ethyl, 4-(6-hexanoylaminophenyl)butyl,2-methylthiobenzyl, 3-methylthiobenzyl, 2-(4-methylthiophenyl)-ethyl,2-ethylthiobenzyl, 1-(3-ethylthiophenyl)ethyl,3-(4-ethylthiophenyl)propyl, 6-(4-isopropylthiophenyl)-hexyl,4-(4-hexylthiophenyl)butyl,1,1-dimethyl-2-(3,4-dimethylthiophenyl)ethyl,5-(3,4-diethylthiophenyl)pentyl, 6-(3,5-dimethylthiophenyl)hexyl,2-methyl-3-(2,5-dimethylthiophenyl)propyl, 3-methyl-4-chlorobenzyl,2-chloro-6-methylbenzyl, 2-methoxy-3-chlorobenzyl,phenyl(4-chlorophenyl)methyl, di(4-methylphenyl)methyl,phenyl(3-methoxyphenyl)methyl, 3,4,5-trimethoxybenzyl, 2-(3,4,5-trimethoxyphenyl)ethyl, 3,4,5-trimethylbenzyl,3,4-ethylenedioxybenzyl, 2,3-methylenedioxybenzyl, 1-(3,4-methylenedioxyphenyl)ethyl, 3-(3,4-methylenedioxyphenyl)propyl,6-(3,4-methylenedioxyphenyl)hexyl, 3,4,5-trichlorobenzyl,3,4-methylenedioxybenzyl, 2-(3,4-methylenedioxyphenyl)ethyl,2-(3,4-ethylenedioxyphenyl)-ethyl, 2-(2,3-methylendioxyphenyl)ethyl,2-(3,4-trimethylenedioxyphenyl)ethyl and4-(3,4-methylenedioxyphenyl)butyl groups and the like.

The expression "a benzoyl group (which may have, on the phenyl ring, 1to 3 substituents selected from the group consisting of a lower alkylgroup, a lower alkoxy group, a halogen atom, a nitro group and a cyanogroup, or said benzoyl group may have, on the phenyl ring, a loweralkylenedioxy group as the substituent)" means a benzoyl group which mayhave, on the phenyl ring, 1 to 3 substituents selected from the groupconsisting of a straight chain or branched chain alkyl group having 1 to6 carbon atoms, a straight chain or branched chain alkoxy group having 1to 6 carbon atoms, a halogen atom, a nitro group and a cyano group, orsaid benzoyl group may have, on the phenyl ring, an alkylenedioxy grouphaving 1 to 4 carbon atoms, and the examples including 2-chlorobenzoyl,3-chlorobenzoyl, 4-chlorobenzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl,4-fluorobenzoyl, 2-bromobenzoyl, 3-bromobenozoyl, 4-bromobenzoyl,2-iodobenzoyl, 3-iodobenzoyl, 4-iodobenzoyl, 3,5 -dichlorobenzoyl,2,6-dichlorobenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl,3,5-dibromobenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl,2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 3-isopropylbenzoyl,4-hexylbenzoyl, 3,4-dimethylbenzoyl, 2,5-dimethylbenzoyl,2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl,3-ethoxybenzoyl, 4-ethoxybenzoyl, 4-isopropoxybenzoyl,4-hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 3,4-diethoxybenzoyl,2,5-dimethoxybenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitrobenzoyl,2,4-dinitrobenzoyl, 2-cyanobenzoyl, 3-cyanobenzoyl, 4-cyanobenzoyl,2,4-dicyanobenzoyl, 3,4-methylenedioxybenzoyl, 3,4-ethylenedioxybenzoyl,2,3-methylenedioxybenzoyl, 3,4-trimethylenedioxybenzoyl,2,3-tetramethylenedioxybenzoyl, 3-methyl-4-chlorobenzoyl,2-chloro-6-methylbenzoyl, 2-methoxy-3-chlorobenzoyl,3,4,5-trimethoxybenzoyl, 3,4,5-trimethylbenzoyl and3,4,5-trichlorobenzoyl groups and the like.

The expression "a phenyl-sulfonyl group (which may have, on the phenylring, 1 to 3 lower alkyl groups as the substituents)" means aphenylsulfonyl group which may have, on the phenyl ring, 1 to 3 alkylgroup having 1 to 6 carbon atoms as the substituents, and the examplesincluding phenylsulfonyl, toluenesulfonyl, xylenesulfonyl,trimethylbenzenesulfonyl, ethylbenzenesulfonyl,isopropylbenzenesulfonyl, butylbenzenesulfonyl and hexylbenzenesulfonylgroups and the like.

The expression "a phenyl-lower alkyl group which may have 1 to 3substituents selected from the group consisting of a lower alkoxy groupand a halogen atom on the phenyl ring, or said phenyl-lower alkyl groupmay have a lower alkylenedioxy group as the substituent on the phenylring" means a straight chain or branched chain alkyl group having 1 to 6carbon atoms, to which one or two phenyl groups are attached, saidphenyl group may have 1 to 3 substituents selected from the groupconsisting of a straight chain or branched chain alkoxy group having 1to 6 carbon atoms and a halogen atom, or said phenyl group may have astraight chain or branched chain alkylenedioxy group having 1 to 4carbon atoms as the substituents, and the examples including benzyl,2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl,2-methyl-3-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl,3,3-diphenylpropyl, 1,1-dimethyl-2,2-diphenylethyl, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, 3-ethoxybenzyl, 2-propoxybenzyl,3-isopropoxybenzyl, 4-tert-butoxybenzyl, 2-(3-methoxyphenyl)ethyl,2-(4-methoxyphenyl)ethyl, 2-(2-ethoxyphenyl)ethyl,2-(3-butoxyphenyl)ethyl, 1-(4-ethoxyphenyl)ethyl,3-(2-methoxypheny)propyl, 2-methyl-3-(4-methoxyphenyl)propyl,6-(4-methoxyphenyl)-hexyl, 2-chlorobenzyl, 3-chlorobenzyl,4-bromobenzyl, 2-iodobenzyl, 3-fluorobenzyl, 2-(3-chlorophenyl)ethyl,2-(4-chlorophenyl)ethyl, 2-(2-bromophenyl)ethyl, 2-(3-iodophenyl)ethyl,1-(4-chlorophenyl)ethyl, 1-(3-bromophenyl)ethyl,3-(2-chlorophenyl)propyl, 3-(4-chlorophenyl)propyl,3-(3-bromophenyl)propyl, 3-(4-iodophenyl)propyl,5-(3-chlorophenyl)pentyl, 2,3-methylenedioxybenzyl,3,4-methylenedioxybenzyl, 2,3-ethylenedioxybenzyl,3,4-ethylenedioxybenzyl, 3,4-trimethylenedioxybenzyl,2-(2,3-methylenedioxyphenyl)ethyl, 2-(3,4-ethylenedioxypheny)ethyl,1-(3,4-methylendioxyphenyl)ethyl, 3-(2,3-methylenedioxyphenyl)propyl,3-(3,4-ethylenedioxyphenyl)propyl,1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethyl,2-methyl-3-(3,4-ethylenedioxyphenyl)propyl, 2,3-dimethoxybenzyl,2,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2,4-diethoxybenzyl,2-(3,4-diethoxyphenyl)ethyl, 2-(3,4,5-trimethoxyphenyl)ethyl,3-(2,3-dimethoxyphenyl)propyl, 3-(3-methoxy-4-ethoxyphenyl)propyl,1,1-dimethyl-2-(3,4,5-trimethoxyphenyl)ethyl,5-(3,4-dimethoxyphenyl)pentyl, 2,3-dichlorobenzyl, 3,4-dichlorobenzyl,3,4,5-trichlorobenzyl, 2,4-dibromobenzyl, 3,4-diiodobenzyl,3,4-difluorobenzyl, 2-chloro-3-bromobenzyl, 2-(2,3-dichlorophenyl)ethyl,2-(3,4,5-trichlorophenyl)ethyl, 2-(3,4-dibromophenyl)ethyl,2-(2,4-diiodophenyl)ethyl, 1-(3,4-dichlorophenyl)ethyl,1-(3,4,5-tribromophenyl)ethyl, 3-2,4-dichlorophenyl)propyl,3-(3,4-dibromophenyl)propyl and 5-(3,4-dichlorophenyl)pentyl groups andthe like.

The expression "a lower alkoxy group" means a straight chain or branchedchain alkoxy group having 1 to 6 carbon atoms, and the examplesincluding methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertbutoxy,pentyloxy and hexyloxy groups and the like.

The expression "a halogen atom" means a fluorine, chlorine, brommine andiodine atoms.

The expression "a lower alkylthio group" means a straight chain orbranched chain alkylthio group having 1 to 6 carbon atoms, and theexamples including methylthio, ethylthio, propylthio, isopropylthio,butylthio, tert-butylthio, pentylthio and hexylthio group and the like.

The expression "a lower alkylenedioxy group" means a straight chain orbranched chain alkylenedioxy group having 1 to 4 carbon atoms, and theexamples including methylenedioxy, ethylenedioxy and trimethylenedioxygroups and the like.

The expression "5- or 6-membered saturated heterocyclic ring" formed byR² and R³ including 1-pyrrolidinyl, 1-piperidyl, morpholino,1-piperazinyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidyl,2-methyl-1-piperidyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl,4-butyl-1-piperazinyl, 4-isopropyl-1-piperazinyl,4-tert-butyl-1-piperazinyl, 4-sec-butyl-1-piperazinyl,4-pentyl-1-piperazinyl, 4-hexyl-1-piperazinyl, 4-benzylpyrrolidino,4-benzyl-1-piperidyl, 3-benzylmorpholino, 4-benzyl-1-piperazinyl,3-(2-phenylethyl)-1-piperidyl, 4-(1-phenylethyl)-1-piperidyl,4-(3-phenylpropyl)-1-piperazinyl, 4-(4-phenylbutyl)-1-piperidyl,3-(6-phenylhexyl)-1-piperidyl and 4-(4-phenylbutyl)-1-piperazinyl groupsand the like.

The expression "a lower alkanoylamino group" means an amino group havinga straight chain or branched chain alkanoyl group having 1 to 6 carbonatoms as the substituent, and the examples including formylamino,acetylamino, propionylamino, butyrylamino, isobutyrylamino,pentanoylamino, tert-butylcarbonylamino and hexanoylamino groups and thelike.

The expression "a cycloalkyl group" means a cycloalkyl group having 3 to8 carbon atoms, and the examples including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl group and the like.

The substituted position of the side chain represented by the formula,##STR13## is 5-, 6-, 7- or 8-position in the carbostyril skeleton.

The expression "a benzoyl-lower alkyl group (which may have, on thephenyl ring, 1 to 3 substituents selected from the group consisting of ahalogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy groupand a lower alkanoylamino group)" means a straight chain or branchedchain alkyl group having 1 to 6 carbon atoms, to which a benzoyl groupis attached, said benzoyl group may have, on the phenyl ring, 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxy group, a straight chain or branched chain alkyl group having 1to 6 carbon atoms, a straight chain or branched chain alkoxy grouphaving 1 to 6 carbon atoms, a straight chain or branched chainalkanoylamino group having 1 to 6 carbon atoms in the alkyl moiety, andthe examples including benzoylmethyl, 2-benzoylethyl, 3-benzoylpropyl,6-benzoylhexyl, 4-benzoylbutyl, (2-methoxybenzoyl)methyl,(3-methoxybenzoyl)methyl, 2-(4-methoxybenzoyl)ethyl,2-ethoxybenzoylmethyl, 1-(3-ethoxybenzoyl)ethyl,3-(4-ethoxybenzoyl)propyl, 6-(4-isopropoxybenzoyl)hexyl,4-(4-hexyloxybenzoyl)butyl, 1,1-dimethyl-2-(3,4-dimethoxybenzoyl)ethyl,5-benzoylpentyl, 5-(3,4-diethoxybenzoyl)pentyl,6-(3,4,5-trimethoxybenzoyl)hexyl,2-methyl-3-(2,5-dimethoxybenzoyl)propyl, (2-chlorobenzoyl)methyl,(3-bromobenzoyl)methyl, (4-iodobenzoyl)methyl, 2-(4-fluorobenzoyl)ethyl,1-(3-chlorobenzoyl)ethyl, 6-(4-bromobenzoyl)hexyl,5-(3,4-dichlorobenzoyl)pentyl,1,1-dimethyl-2-(2,5-dibromobenzoyl)propyl,(3,4,5-trichlorobenzoyl)-methyl, (2-methylbenzoyl)methyl,(3-methylbenzoyl)-methyl, 2-(4-methylbenzoyl)ethyl,(2-ethylbenzoyl)-methyl, 1-(3-ethylbenzoyl)ethyl,3-(4-ethylbenzoyl)-propyl, 6-(4-isopropylbenzoyl)hexyl,4-(4-hexylbenzoyl)butyl, 1,1-dimethyl-2-(3,4-dimethylbenzoyl)ethyl,5-(3,4-diethylbenzoyl)pentyl, 6-(3,5-dimethylbenzoyl)-hexyl,2-methyl-3-(2,5-dimethylphenoxy)propyl, (2-acetylaminobenzoyl)methyl,(3-formylaminobenzoyl)methyl, 1-(3-propionylaminobenzoyl)ethyl,6-(4-n-butyrylaminobenzoyl)hexyl, 2-(5-pentanoylaminobenzoyl)ethyl,4-(6-hexanoylaminobenzoyl)butyl, (2-hydroxybenzoyl)-methyl,(3-hydroxybenzoyl)methyl, (4-hydroxybenzoyl)-methyl,2-(4-hydroxybenozyl)ethyl, 1-(3-hydroxybenzoyl)ethyl,6-(4-hydroxybenzoyl)hexyl, 5-(3,4-dihydroxybenzoyl)pentyl,1,1-dimethyl-2-(2,5-dihydroxybenzoyl)propyl and(3,4,5-trihydroxybenzoyl)methyl groups and the like.

The expression "a phenyl-lower alkanoyl group (which may have, on thephenyl ring, 1 to 3 lower alkoxy groups as the substituents)" means analkanoyl group having 2 to 6 carbon atoms, to which a phenyl group isattached, said phenyl group may have 1 to 3 straight chain or branchedchain alkoxy groups having 1 to 6 carbon atoms as the substituents, andthe examples including phenylacetyl, 3-phenylpropionyl,2-phenylpropionyl, 4-phenylbutyryl, 2,2-dimethyl-3-phenylpropionyl,5-phenylpentanoyl, 6-phenylhexanoyl, 3-methyl-4-phenylbutyryl,(2-methoxyphenyl)acetyl, (3-methoxyphenyl)acetyl,(4-methoxyphenyl)acetyl, (3-ethoxyphenyl)acetyl,(2-propoxylpheny)acetyl, (3-isopropoxyphenyl)acetyl,(4-tert-butoxyphenyl)acetyl, 3-(3-methoxyphenyl)propionyl,3-(4-methoxyphenyl)-propionyl, 3-(2-ethoxyphenyl)propionyl,3-(3-butoxyphenyl)propionyl, 4-(2-methoxyphenyl)butyryl,3-methyl-4-(4-methoxyphenyl)butyryl, 6-(4-methoxyphenyl)-hexanoyl,(2,3-dimethoxyphenyl)acetyl, (2,4-dimethoxyphenyl)acetyl,(3,4,5-trimethoxyphenyl)acetyl, (2,4-diethoxyphenyl)acetyl,3-(3,4-diethoxyphenyl)propionyl, 3-(3,4,5-trimethoxyphenyl)propionyl,4-(2,3-dimethoxyphenyl)butyryl, 4-( 3-methoxy-4-ethoxyphenyl)butyryl,2,2-dimethyl-3-(3,4,5-trimethoxyphenyl)propionyl and6-(3,4-dimethoxyphenyl)hexanoyl groups and the like.

The expression "a lower alkyl group which may have hydroxy group(s) orhalogen atom(s) as the substituent(s)" means a straight chain orbranched chain alkyl group having 1 to 6 carbon atoms which may have, asthe substituent(s), hydroxy group(s), or halogen atom(s), and theexamples including chloromethyl, boromomethyl, iodomethyl, fluoromethyl,2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloropropyl,2-fluoropropyl, 3-iodopropyl, 1-methyl-2-chloroethyl, 2-bromobutyl,3-bromobutyl, 4-bromobutyl, 3-chlorobutyl, 2-iodobutyl, 4-fluorobutyl,1,1-dimethyl-2-chlorobutyl, 2-chloropentyl, 3-chloropentyl,4-bromohexyl, 6-chlorohexyl, 5-bromopentyl, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxypropyl,4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl and 6-hydroxyhexylgroups and the like.

The expression "a phenyl-lower alkenylcarbonyl group (which may have, onthe phenyl ring, 1 to 3 substituents selected from the group consistingof a halogen atoms and a lower alkoxy group)" means a straight chain orbranched chain alkenylcarbonyl group having 3 to 6 carbon atoms, towhich a phenyl group is attached, said phenyl group may have 1 to 3substituents selected from the group consisting of a halogen atom, alower alkoxy group having 1 to 6 carbon atoms, and the examplesincluding cinnamoyl, 4-phenyl-3-butenoyl, 4-phenyl-2-butenoyl,5-phenyl-4-pentenoyl, 5-phenyl-3-pentenoyl, 5-phenyl-2-pentenoyl,6-phenyl-5-hexenoyl, 6-phenyl-4-hexenoyl, 6-phenyl-3-hexenoyl,6-phenyl-2-hexenoyl, 2-methyl-4-phenyl-3-butenyl, 2-methylcinnamoyl,1-methylcinnamoyl, 2-chlorocinnamoyl, 3-chlorocinnamoyl,4-chlorocinnamoyl, 2-fluorocinnamoyl, 3-fluorocinnamoyl,4-fluorocinnamoyl, 2-bromocinnamoyl, 3-bromocinnamoyl, 4-bromocinnamoyl,2-iodocinnamoyl, 3-iodocinnamoyl, 4-iodocinnamoyl,3,5-dichlorocinnamoyl, 2,6-dichlorocinnamoyl, 3,4-dichlorocinnamoyl,3,4-difluorocinnamoyl, 3,5-dibromocinnamoyl, 3,4,5-trichlorocinnamoyl,4-fluorophenyl-3-butenoyl, 4-(3-chlorophenyl)-2-butenoyl,5-(4-bromophenyl)-4-pentenoyl, 6-(3,4-dichlorophenyl)-5-hexenoyl,2-methyl-(2,5-dibromophenyl)cinnamoyl,1-methyl-(3-chlorophenyl)cinnamoyl, 6-(3,4,5-tribromophenyl)-3-hexenoyl,2-methoxycinnamoyl, 3-methoxycinnamoyl or 4-methoxycinnamoyl,2-ethoxycinnamoyl, 3-ethoxycinnamoyl or 4-ethoxycinnamoyl,2-propoxycinnamoyl, 3-propoxycinnamoyl or 4-propoxycinnamoyl,2-butoxycinnamoyl, 3-(tert-butoxy)cinnamoyl, 4-pentyloxycinnamoyl,3-hexyloxycinnamoyl, 3,5-dimethoxycinnamoyl, 2,6-dimethoxycinnamoyl,3,4-dimethoxycinnamoyl, 3,4-diethoxycinnamoyl, 3,5-diethoxycinnamoyl,3,4,5-trimethoxycinnamoyl, 4-ethoxyphenyl-3-butenoyl,4-(3-tert-butoxyphenyl)-2-betenoyl, 5-(4-hexyloxyphenyl)-4-pentenoyl,6-(3,4-dimethoxyphenyl)-5-hexenoyl,2-methyl-(2,5-diethoxyphenyl)cinnamoyl,1-methyl-(3-methoxyphenyl)cinnamoyl, and6-(3,4,5-triethoxyphenyl)-3-hexenyl groups and the like.

The expression "a lower alkanoyl-lower alkyl group" means a straightchain or branched chain alkyl group having 1 to 6 carbon atoms, to whicha straight chain or branched chain alkanoyl group having 1 to 6 carbonatoms is attached, and the examples including acetylmethyl,2-acetylethyl, 2-acetylpropyl, 3-acetylpropyl, 4-acetylbutyl,3-acetylbutyl, 5-acetylpentyl, 6-acetylhexyl, 2-propionylethyl,3-formylpropyl, 2-butyrylpropyl, 4-isobutyrylbutyl, 2-pentanoylethyl,tert-butylcarbonylmethyl, 2-hexanoylethyl and 1,1-dimethyl-2-acetylethylgroups and the like.

The expression "a lower alkoxycarbonyl-lower alkyl group" means astraight chain or branched chain alkyl group having 1 to 6 carbon atoms,to which a straight chain or branched chain alkoxycarbonyl group having1 to 6 carbon atoms is attached, and the examples includingmethoxycarbonylmethyl, 2-(methoxycarbonyl)ethyl, ethoxycarbonylmethyl,1-(ethoxycarbonyl)-ethyl, 3-(methoxycarbonyl)propyl,propoxycarbonylmethyl, 2-(propoxycarbonyl)methyl,4-(propoxycarbonyl)-butyl, butoxycarbonylmethyl,1-(butoxycarbonyl)ethyl, tert-butoxycarbonylmethyl,3-(tert-butoxycarbonyl)-propyl, pentyloxycarbonylmethyl,2-(hexyloxycarbonyl)-ethyl, 5-(methoxycarbonyl)pentyl and6-ethoxycarbonyl)-hexyl groups and the like.

Carbostyril derivatives of the present invention can be preparedaccording to various processes such as for example expressed by thefollowing reaction process formula-1: ##STR14## wherein R¹, R², R³ andthe carbon-carbon bond between 3- and 4-positions in the carbostyrilskeleton are the same as defined previously.

According to reaction process formula-1, carbostyril derivativerepresented by the general formula (1) can be prepared by reacting aknown carboxylic acid derivative or its carboxylic group-activatedcompound represented by the general formula (2) with an amine or itsamino group-activated compound represented by the general formula (3)under a conventional amide bond forming reaction condition.

As to the amide bond forming reaction condition, the following methodscan be exemplified, for example, (a) mixed acid anhydride method: e.g.,a method by reacting a carboxylic acid (2) with an alkyl halocarboxylicacid to form a mixed acid anhydride, then the mixed acid anhydride isreacted with an amine (3); (b) activated ester method: e.g., a method byreacting an activated ester of a carboxylic acid (2), for examplep-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazolester, with an amine (3); (c) carbodiimide method: e.g., a method bydehydro-condensing a carboxylic acid (2) with an amine (3) in thepresence of a dehydrating agent, for example, dicyclohexylcarbodiimide,carbonylidiimidazol or the like; (d) carboxylic acid halide method:e.g., a method by changing a carboxylic acid (2) into an acid halideform, then the halide of carboxylic acid (2) is reacted with an amine(3); (e) a method by reacting a carboxylic acid (2) with a dehydratingagent, for example, acetic anhydride, to obtain a carboxylic acidanhydride, then the carboxylic acid anhydride is reacted with an amine(3); (f) a method by reacting an ester of a carboxylic acid (2), beingprepared from it with a lower alcohol, with an amine (3) under a highpressure and high temperature condition; (g) a method by activating acarboxylic acid (2) with a phosphorus compound, for example,triphenylphosphine or diethylchlorophosphate, said activated compound ofcarboxylic acid (2) is reacted with an amine (3).

In the mixed acid anhydride method (a), the mixed acid anhydride isobtained by a conventional Schotten-Baumann reaction, and generally themixed acid anhydride is reacted with an amine (3), without beingseparated from the reaction mixture of Schotten-Baumann reaction, toobtain carbostyril derivative (1) of the present invention. TheSchotten-Baumann reaction is carried out in the presence of a basiccompound, for example, an organic basic compound such as triethylamine,trimethylamine pyridine, dimethylaniline, N-methylmorpholine,4-dimethylaminopyridine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN),1,5-diazabicyclo[5,4,0]undecene-5 (DBU), 1,4-diazabicyclo[2,2,2]octane(DABCO) or the like, an inorganic basic compound, such as potassiumcarbonate, sodium carbonate, potassium hydrogencarbonate, sodiumhydrogencarbonate or the like, at a temperature about -20° to 100° C.,preferably, at 0° to 50° C., for about 5 minutes to 10 hours,preferably, for 5 minutes to 2 hours. Reaction of the thus obtainedmixed acid anhydride with an amine (3) is carried out at a temperatureof -20° to 150° C., preferably, at 10° to 50° C., for about 5 minutes to10 hours, preferably, for 5 minutes to 5 hours.

The above-mentioned mixed acid anhydride method is generally carried outin the absence or presence of a suitable solvent usually used for thistype of mixed acid anhydride method, concretely a halogenatedhydrocarbon for example, methylene chloride, chloroform, dichloroethaneor the like, an aromatic hydrocarbon for example, benzene, toluene,xylene or the like, an ether for example, diethyl ether,tetrahydrofuran, dimethoxyethane or the like, an ester for example,methyl acetate, ethyl acetate or the like, an aprotic polar solvent forexample, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphorictriamide or the like can be exemplified.

As to the alkylhalocarboxylic acid used for preparing above-mentionedmixed acid anhydride can be exemplified such as methyl chloroformate,methyl bromoformate, ethyl chloroformate ethyl bromoformate, isobutylchloroformate or the like, and generally said alkylhalocarboxylic acidis used in at least an equimolar amount, preferably, 1 to 2 times themolar quantity of the carboxylic acid (2). The amine (3) is generallyused in at least an equimolar amount, preferably 1 to 2 times the molarquantity of the carboxylic acid (2).

The activated ester method as mentioned (b) as above, for example, inusing N-hydroxysuccinimide ester, the reaction is generally carried outin a suitable inert solvent. As to the solvent, concretely a halogenatedhydrocarbon for example, methylene chloride, chloroform, dichloroethaneor the like, an aromatic hydrocarbon for example, benzene, toluene,xylene or the like, an ether for example, diethyl ether, terahydrofuran,dimethoxyethane or the like, an ester for example, methyl acetate, ethylacetate or the like, an aprotic polar solvent for example,N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamideor the like can be exemplified.

The reaction is carried out at a temperature of 0° to 150° C.,preferably at 10° to 100° C., for 5 to 30 hours.

The amine (3) is usually used in an equimolar amount, preferably 1 to 2times the molar quantity of the N-hydroxysuccinimide ester.

In the carboxylic acid halide method (d) as above, that is by reacting acarboxylic acid halide with an amine (3), the reaction can be carriedout in a suitable solvent in the presence of a dehydrohalogenatingagent. As to the dehydorhalogenating agent, a common basic compoundwhich is known widely can be used, for example, a basic compound used inthe above-mentioned Schotten-Baumann reaction can also be used,additionally sodium hydroxide, potassium hydroxide, sodium hydride,potassium hydride, silver carbonate, an alcoholate, for example, sodiummethylate or sodium ethylate can be exemplified. Saiddehydrohalogenating agent is used with an excess amount of an amine (3).As to the solvent used in the carboxylic acid halide method, any solventused in the abovementioned Schotten-Baumann resction can also be used,further an alcohol such as, methanol, ethanol, propanol, butanol,3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve or the like,pyridine, acetone, acetonitrile or the like or a mixture of the solventsin combination of two or more of the above-mentioned solvents can alsobe exemplified.

There is not any specific restriction to the ratio of the amount of anamine (3) to the amount of a carboxylic acid halide in the abovereaction, the ratio can be selected from a wide range, and the lattermay be used at least in an equimolar amount, preferably an equimolar to2 times the molar quantity to the former.

The reaction is generally carried out at a temperature of -30° to 180°C., preferably at about 0° to 150° C., and the reaction is completed for5 minutes to 30 hours.

The carboxylic acid halide used in this reaction can be prepared byreacting a carboxylic acid (2) with a halogenating agent in the absenceor presence of a solvent. As to the solvent, any solvent which does notgive adverse effect to the reaction can be used, for example an aromatichydrocarbon such as benzene, toluene, xylene or the like, a halogenatedhydrocarbon such as chloroform, methylene chloride, carbon tetrachlorideor the like, an ether such as dioxane, tetrahydrofuran, diethyl ether orthe like, dimethylformamide, dimethyl sulfoxide or the like can beexemplified. As to the halogenating agent, a common halogenating agentwhich changes hydroxy group in the carboxyl group can be used, forexample thionyl chloride, phosphorus oxychloride, phosphorus oxybromide,phosphorus pentachloride, phosphorus pentabrimide or the like can beexemplified.

There is not any specific restriction to the ratio of the amount of acarboxylic acid (2) to the amount of a halogenating agent in thereaction, the ratio can be selected from a wide range, when the reactionis carried out in the absence of a solvent, the latter is used in anexcess amount to the former, and when the reaction is carried out in thepresence of a solvent, the latter is used at least in an equimolaramount, preferably, 2 to 4 times the molar quantity to the former. Thereaction temperature (and the reaction time) may not be restricted, andgenerally the reaction can be carried out at a room temperature to 100°C., preferably 50° to 80° C., for 30 minutes to 6 hours.

In the method (g) by activating a carboxylic acid (2) with a phosphoruscompound, for example, triphenylphosphine or diethylchlorophosphate,then said activated compound of carboxylic acid (2) is reacted with anamine (3), the reaction can be carried out in a suitable solvent. As tothe solvent, any solvent which does not give adverse effect to thereaction can be used, concretely for example, a halogenated hydrocarbonsuch as methylene chloride, chloroform, dichloroethane or the like, anaromatic hydrocarbon, such as benzene, toluene, xylene or the like, anether such as diethyl ether, tetrahydrofuran, dimethyloxyethane or thelike, an ester such as methyl acetate, ethyl acetate or the like, anaprotic polar solvent such as N,N-dimethylformamide, dimethyl sulfoxide,hexamethylphosphoric triamide or the like can be exemplified.

In this reaction, since an amine (3) per se performs as a basiccompound, the reaction can be proceeded smoothly, and further, ifnecessary other basic compound, for example an organic basic compoundsuch as triethylamine, trimethylamine, pyridine, dimethylaniline,N-methylmorpholine, DBN, DBU, DABCO or the like, an inorganic basiccompound, such as potassium carbonate, sodium carbonate, potassiumhydrogencarbonate, sodium hydrogencarbonate or the like can be used.

The reaction can be carried out at a temperature of about 0° to 150° C.,preferably at about 0° to 100° C., and the reaction time is about 1 to30 hours. The ratio of the amounts of a phosphorus compound and an amine(3) to the amount of a carboxylic acid (2) is generally at least in anequimolar quantity, preferably 1 to 3 times the molar quantity.

Among the carbostyril derivatives of the present invention, compoundsrepresented by the general formulas (1-a), (1-b) and (1-c) can beprepared, respectively by methods according to reaction processformulas-2 to -5 as follows: ##STR15## wherein R¹ and the carbon-carbonbond between 3- and 4-positions in the carbostyril skeleton are the sameas defined previously; R⁴ is a lower alkanoyl group, a loweralkoxycarbonyl group, a furoyl group, a benzoyl group (which may have,on the phenyl ring, 1 to 3 substituents selected from the groupconsisting of a lower alkyl group, a lower alkoxy group, a halogen atom,a nitro group and a cyano group, or said benzoyl group may have, on thephenyl ring, a lower alkylenedioxy group as the substituent), aphenyl-lower alkanoyl group [which may have, on the phenyl ring, 1 to 3lower alkoxy group as the substituents) or a phenyl-loweralkenylcarbonyl group (which may have, on the phenyl ring, 1 to 3substituents selected from the group consisting of a halogen atom and alower alkoxy group); X¹ is a hydroxy group.

A compound represented by the general formula (1-a) of the presentinvention can be prepared by reacting a compound (4) or an activatedcompound of its amino group, with a compound (5) or an activatedcompound of its carboxyl group. The above-mentioned reaction can becarried out by a procedure and under conditions similar to thosementioned in the reaction of a compound (2) or an activated compound ofits carboxyl group, with an amine derivative (3) or an activatedcompound of its amino group, used in reaction process formula-1.##STR16## wherein R¹ and the carbon-carbon bond between 3- and4-positions in the carbostyril skeleton are the same as defined aspreviously; R⁵ is a lower alkyl group, a lower alkoxycarbonyl-loweralkyl group, a lower alkenyl group, a lower alkynyl group, cycloalkylgroup, a cycloalkyl-lower alkyl group, a lower alkylsulfonyl group, aphenoxy-lower alkyl group (which may have, on the phenyl ring, 1 to 3substituents selected from the group consisting of a halogen atom, alower alkoxy group and a lower alkyl group, or said phenoxy-lower alkylgroup may have, on the phenyl ring, a lower alkylenedioxy group as thesubstituent), a substituted lower alkyl group (having one substituentselected from the group consisting of a cyano group, a benzoyloxy group(which may have 1 to 3 lower alkoxy groups on the phenyl ring), ahydroxy group a lower alkanoyloxy group, a halogen atom and a carbamoylgroup), a lower alkanoyl-lower alkyl group, a phenyl-lower alkyl group(which may have, on the phenyl ring, 1 to 3 lower alkyl groups as thesubstuents) or a benzoyl-lower alkyl group (which may have, on thephenyl ring, 1 to 3 substituents selected from the group consisting of ahalogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy groupand a lower alkanoylamino group); X² is a halogen atom, a loweralkanesulfonyloxy group, an arylsulfonyloxy group or anaralkylsulfonyloxy group.

Carbostyril derivative represented by the general formula (1-b) can beprepared by reacting a compound represented by the general formula (4)with a compound represented by the general formula (6). This reactioncan be carried out by procedures under the conditions similar to thosedescribed in the reaction of carboxylic acid halide with an amine (3) asmentioned above.

In the compound represented by the general formula (6), in thedefinitions for the symbol X², the halogen atom is specifically achlorine, fluorine, bromine or iodine atom, the lower alkanesulfonyloxygroup can be exemplified such as methanesulfonyloxy, ethanesulfonyloxy,isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy,tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy or thelike; the arylsulfonyloxy group is specifically a substituted orunsubstituted arylsulfonyloxy group such as phenylsulfonyloxy,4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy,3-chlorophenylsulfonyloxy, α-naphthylsulfonyloxy group or the like; thearalkylsulfonyloxy group is specifically a substituted or unsubstitutedaralkylsulfonyloxy group such as benzylsulfonyloxy,2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy,4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy,4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy,3-chlorobenzylsulfonyloxy, α-naphthylmethylsulfonyloxy group or thelike. ##STR17## wherein R¹ and the carbon-carbon bond between 3- and4-positions in the carbostyril skeleton are the same as definedpreviously; R⁶ is a lower alkyl group, a lower alkoxycarbonyl-loweralkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkylgroup, a cycloalkyl-lower alkyl group, a phenoxy-lower alkyl group(which may have, on the phenyl ring, 1 to 3 substituents selected fromthe group consisting of a halogen atom, a lower alkoxy group and a loweralkyl group, or said phenoxy-lower alkyl group may have, on the phenylring, a lower alkylenedioxy group as the substituent) a substitutedlower alkyl group (having one substituent selected from the groupconsisting of a cyano group, a benzoyloxy group (which may have 1 to 3lower alkoxy groups on the phenyl ring), a hydroxy group, a loweralkanoyloxy group, a halogen atom and a carbamoyl group), a loweralkanoyl-lower alkyl group, a phenyl-lower alkyl group (which may have,on the phenyl ring, 1 to 3 substituents selected from the groupconsisting of a lower alkyl group, a lower alkoxy group, a halogen atom,a nitro group, an amino group, a lower alkanoylamino group and a loweralkylthio group, or said phenyl-lower alkyl group may have, on thephenyl ring, a lower alkylenedioxy group as the substituent) or abenzoyl-lower alkyl group (which may have, on the phenyl ring, 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxy group, a lower alkyl group, a lower alkoxy group and a loweralkanoylamino group), X is the same as defined in X¹ and X².

A compound represented by the general formula (1-c) of the presentinvention can be prepared by reacting a compound of the general formula(2) with a compound of the general formula (7) to obtain a compound ofthe general formula (8), then reacting a compound of the general formula(8) with a compound of the general formula (9). The reaction in theabove-mentioned first step is carried out by procedure under theconditions similar to those described in the reaction of a compound ofthe general formula (2) with a compound of the general formula (3). Thereaction in the second step followed by the above-mentioned first stepcan be carried out the following procedure according to the type of X inthe general formula (8). Thus, when a compound of the general formula(8) wherein X is a halogen atom, a lower alkanesulfonyloxy group, anarylsulfonyloxy group or an aralkylsulfonyloxy group, is used, thereaction of a compound of the general formula (8) with a compound of thegeneral formula (9) is carried out in a suitable incert solvent in theabsence or presence of a basic condensing agent. As to the inertsolvent, an aromatic hydrocarbon for example benzen, toluene, xylene orthe like, a lower alcohol for example methanol, ethanol, isopropanol,butanol or the like, acetic acid, ethyl acetate, dimethyl sulfoxide,dimethylformamide, hexamethylphosphoryl triamide or the like can beexemplified. As to the basic condensing agent, a carbonate for examplepotassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate or the like, a metal hydroxide for example sodiumhydroxide, potassium hydroxide or the like, a metal alcoholate forexample sodium methylate, sodium ethylate or the like, a tertiary aminefor example pyridine, triethylamine or the like can be exemplified.

There is not any specific restriction to the ratio of the amount of acompound of the general formula (8) to the amount of a compound of thegeneral formula (9) in the above reaction, and the ratio can suitably beselected from a wide range, generally the latter may be used at least inan equimolar amount, preferably an equimolar to 5 times the molarquantity to the former.

The reaction is carried out generally at 40° to 120° C., preferably 50°to 100° C., and the reaction is completed within about 5 to 30 hours.

On the other hand, when a compound of the general formula (8) wherein Xis a hydrogen group is used, the reaction of a compound of generalformula (8) with a compound of the general formula (9) is carried out inthe presence of a dehydrating-condensing agent in the absence orpresence of a suitable solvent. As to the dehydrating-condensing agent,a condensed phosphoric acid for example a polyphosphoric acid or thelike, a phosphoric acid for example orthophosphoric acid, pyrophosphoricacid, metaphosphoric acid or the like, a phosphorous acid for exampleorthophosphorous acid or the like, a phosphoric acid anhydride forexample phosphorus pentoxide, an acid for example hydrochloric acid,sulfuric acid, boric acid or the like, a metal phosphate for examplesodium phosphate, boron phosphate, ferric phosphate, aluminium phosphateor the like, activated alumina, sodium bisulfate, Raney nickel or thelike can be exemplified. As to the solvent a high boiling point solventfor example dimethylformamide, tetrahydronaphthalene or the like can beexemplified.

There is not any specific restriction to the ratio of the amount of acompound of the general formula (8) to the amount of a compound of thegeneral formula (9) in the above reaction, and the ratio can suitably beselected from a wide range, generally the former may be used in 0.8times the molar quantity or more, preferably 0.8 to 2 times the molarquantity. There is not any specific restriction to the amount of thedehydrating-condensing agent, and the amount can be selected suitablyfrom a wide range, and generally a catalytic amount or more, preferably0.5 to 5 times the molar quantity of the dehydrating-condensing agentcan be used to the equimolar quantity of a compound of the generalformula (8).

The reaction can advantageously be carried out in an inert gas streamfor example in CO₂ or N₂ gas stream for the purpose of to preventoxidation reaction. The reaction is generally carried out under a smallpressure at about 100° to 350° C., preferably at 125° to 255° C. forabout 3 to 10 hours. ##STR18## wherein R¹, R⁶ and the carbon-carbon bondbetween 3- and 4-positions in the carbostyril skeleton are the same asdefined previously.

A compound represented by the general formula (1-c) of the presentinvention can also be prepared by reacting a compound of the generalformula (2) with morpholine (10) to obtain a morpholine derivative (11),then reacting the morpholine derivative (11) with a compound of thegeneral formula (9).

The reaction of a compound of the general formula (2) with morpholine(10) can be carried out by a procedure under the conditions similar tothose described in the reaction of a compound of the general formula (2)with a compound of the general formula (3). The reaction of the obtainedcompound of the general formula (11) with a compound of the generalformula (9) is carried out in the presence of an acid in the absence orpresence of a suitable solvent. As to the solvent, a high boiling pointsolvent such as tetrahydronaphthalene, dimethyl sulfoxide,dimethylformamide, hexamethylphosphoric triamide or the like can beused. As to the acid, hydrochloric acid, sulfuric acid, hydrobromic acidor the like can be used. There is not any specific restriction to theratio of the amount of a compound of the general formula (11) to theamount of a compound of the general formula (9), and the ratio cansuitably be selected from a wide range, generally, the latter may beused at least in an equimolar quantity, preferably an equimolar to 2times the molar quantity to the former. The reaction is generallycarried out at 50° to 250° C., preferably at 150° to 200° C., and thereaction is completed within about 1 to 24 hours.

Among the compounds of the general formula (1) of the present invention,those having substituent other than hydrogen as for the symbol R¹ (acompound of the general formula (1-e)) can be prepared from a compoundhaving a hydrogen atom as for the symbol R¹ (a compound of the generalformula (1-d)) by a method as described in reaction process formula-6 asfollows: ##STR19## wherein R², R³, X² and the carbon-carbon bond between3- and 4-positions in the carbostyril skeleton are the same as definedpreviously; and R^(1') is the same as the definition of R¹ excluding ahydrogen atom.

The reaction of a compound of the general formula (1-d) with a compoundof the general formula (12) may be carried out in a suitable solvent inthe presence of a basic compound. As to the basic substance, sodiumhydride, potassium metal, sodium metal, sodium amide, potassium amide,or the like can be exemplified. As to the solvent, an ether such asdioxane, diethylene glycol dimethyl ether or the like, an aromatichydrocarbon such as toluene, xylene or the like, dimethylformamide,dimethyl sulfoxide, hexamethylphosphoric triamide or the like can beexemplified.

There is not any specific restriction to the ratio of the amount of acompound of the general formula (1-d) to the amount of a compound of thegeneral formula (12) in the above reaction, and the ratio can suitablybe selected from a wide range, generally the latter may be used at leastin an quimolar quantity or more, preferably an equimolar to 2 times themolar quantity to the former. The reaction is generally carried out at0° to 70° C., preferably at 0° C. to a room temperature and the reactionis completed within 0.5 to 12 hours.

Among the compounds represented by the general formula (1), those havingamino group as the substituent on the phenyl ring can easily be preparedby reducing the corresponding compound having nitro group as thesubstituent on the phenyl ring. This reducing reaction can be carriedout under the conditions generally used in reducing an aromatic nitrocompound to the corresponding aromatic amino compound. Morespecifically, the reducing reaction can be carried out by a method usingsodium sulfite or sulfur dioxide as a reducing agent, or a catalyticreducing method using a palladium-carbon or the like as a reducingcatalyst.

In the reaction process formulas-1, -4 and -5 as explained in detail asabove, compounds of the general formula (2), being used for preparingthe objective carbostyril derivative, partially including novelcompounds and said compound of the general formula (2) can be preparedby a method according to reaction process formulas-7 or -8 as follows:##STR20## wherein R¹ and the carbon-carbon bond between 3- and4-position in the carbostyril skeleton are the same as definedpreviously; R³ --H is an aromatic amine; and X^(2') is a halogen atom.

The reaction for obtaining a compound of the general formula (15) can becarried out in the absence or presence of a suitable solvent by reactinga compound of the general formula (13) with an aromatic amine (14). Asto the solvent, any solvent which does not give adverse effect can beused, for example a halogenated hydrocarbon such as methylene chloride,chloroform, dichloromethane or the like, an ether such as diethyl ether,tetrahydrofuran, dimethoxyethane or the like, an ester such as methylacetate, ethyl acetate or the like, an aprotic polar solvent such asN,N-dimethylformamide, dimethyl sulfoxide, hexamethylpohosphorictriamide or the like can be exemplified. As to the aromatic amine,pyridine, quinoline or the like can be exemplified. The amount of thearomatic amine to be used is at least in an equimolar amount, preferablya great excess amount may be used to the compound of the general formula(13). The reaction temperature is 50° to 200° C., preferably 70° to 150°C., and the reaction is completed within 3 to 10 hours. The hydrolysisreaction of a compound of the general formula (15) thus obtained can becarried out in water, by using an inorganic basic compound such assodium hydroxide or potassium hydroxide, or an acid such as hydrochloricacid or hydrobromic acid, at a room temperature to 150° C. for 1 to 10hours. The piperazine derivatives represented by the general formula (3)which are used as another starting material in reaction processformula-1 also including partially novel compounds, and these compoundscan easily be obtained by using piperazine in place of a compound of thegeneral formula (4) in the reaction of a compound of the general formula(4) with a compound of the general formula (5) or (6). ##STR21## whereinR¹ and the carbon-carbon bond between 3- and 4-positions in thecarbostyril skeleton are the same as defined previously; X³ is a halogenatom.

The reaction of a compound of the general formula (16) with a halogen isgenerally carried out in a suitable solvent. As to the solvent to beused, an ether such as tetrahydrofuran, dioxane or the like, acarboxylic acid such as acetic acid, propionic acid or the like, anaromatic hydrocarbon such as benzene or the like, dimethylformamide,dimethyl sulfoxide or the like can be examplified. In carrying out thereaction, calcium carbonate or the like can be added as an deacidifyingagent for removing a hydrogen halide being formed as the by-product.

There is not any specified restriction to the ratio of the amount of acompound of the general formula (17) to the amount of a halogen in thisreaction, and the ratio can be suitably selected from a wide range,generally the latter may be used in 2 to 5 times the molar quantity,preferably 2 to 3 times the molar quantity to the former. The reactionmay be generally carried out at 0° to 50° C., and is completed within aseveral hours to 24 hours.

The reaction for obtaining a compound of the general formula (2) from acompound of the general formula (17) may be carried out in an aqueoussolvent in the presence of a basic compound. As to the basic compound, aknown basic compound can be used for example, alkali metal hydroxide, ora alkaline earth metal hydroxide, such as sodium hydroxide, potassiumhydroxide, calcium hydroxide can be exemplified. There is not anyspecific restriction to the ratio of the amount of a basic compound, andthe ratio can be selected from a wide range, generally 2 times the molarquantity or a great excess quantity of the basic compound may be used tothe compound of the general formula (17). The reaction may be carriedout at 50° to 150° C., preferably 70° to 120° C., and generally thereaction is completed in 1 to 12 hours.

In the reaction process formulas-7 and -8, compounds of the generalformulas (13) and (16) being used as the starting materials includingnovel and known compounds, and they can be prepared respectively bymethods according to reaction process formulas-9, -10a, -11a and -11b.##STR22## wherein X³ is a halogen atom; X⁴ is a hydrogen atom or ahalogen atom; R¹ and the carbon-carbon bond between 3- and 4-positionsin the carbostyril skeleton are the same as defined previously.

The reaction of a compound of the general formula (18) with a compoundof the general formula (19) or (20) is called generally asFriedel-Crafts reaction and the reaction is carried out in a solvent inthe presence of a Lewis acid. As to the solvent to be used in thisreaction, any solvent generally used for this reaction canadvantageously be used, for example carbon disulfide, nitrobenzene,chlorobenzene, dichloromethane, dichlroethane, trichloroethane,tetrachloroethane or the like can be exemplified. As to the Lewis acid,any Lewis acid generally used for this type of reaction can preferablybe used, for example aluminium chloride, zinc chloride, ferric chloride,tin chloride, boron tribromide, boron trifluoride, concentrated sulfuricacid or the like can be used. The amount of Lewis acid being used maysuitably be determined and generally 2 to 6 times the molar quantity,preferably 3 to 4 times the molar quantity of Lewis acid is used to acompound of the general formula (18). The amount of a compound of thegeneral formula (19) or (20) to the amount of a compound of the generalformula (18) may be of at least an equimolar quantity, preferably anequimolar to 3 times the molar quantity to the latter. The reactiontemperature can be suitably selected, and generally 20° to 120° C.,preferably 40° to 70° C. The reaction time may be varied depend on thetype of the starting materials and the catalyst and the reactiontemperature, and generally the reaction can be completed in 0.5 to 24hours. ##STR23## wherein X² is a halogen atom; R^(1') is a lower alkylgroup, a lower alkenyl group, a lower alkynyl group or a phenyl-loweralkyl group; R⁷ is a hydrogen atom or a lower alkyl group; X³ and X⁴ arethe same as defined previously.

The reaction of a compound of the general formula (22) with a compoundof the general formula (19) or (20) can be carried out by a methodsimilar to that described in the reaction of a compound of the generalformula (18) with a compound of the general formula (19) or (20), exceptthe reaction temperature. Thus the reaction may be carried out suitablyat within the range of -50° to 120° C., preferably at 0° to 70° C. Thereaction time may be varied depend on the type of the starting materailsand the catalyst and the reaction temperature, generally the reactioncan be completed in 0.5 to 24 hours. The nitration of a compound (23) isgenerally carried out under conventional conditions of nitration of anaromatic compound in the absence or presence of a suitable inert solventby using a nitration agent. As to the inert solvent, acetic acid, aceticanhydride and concentrated sulfuric acid can be exemplified. As to thenitration agent, fuming nitric acid, concentrated nitric acid, a mixedacid (a mixture of nitric acid with sulfuric acid, fuming sulfuric acid,phosphoric acid or acetic anhydride), a mixture of an alkali metalnitrate, for example potassium nitrate, sodium nitrate, with sulfuricacid can be exemplified. The amount of the nitration agent to be usedmay be of an equimolar quantity or excess quantity to the startingmaterial, and the nitration is generally carried out at a temperaturewithin the range of from -30° C. to a room temperature, preferably atabout -30° C., for 5 minutes to 4 hours.

The carbostyril compound of the general formula (25 is prepared byreducing and ring closing the compound of the general formula (24). Thisreaction can be carried out (1) by reducing the compound (24) with areducing catalyst in a suitable solvent or (2) by reducing the compound(24) in a suitable inert solvent by using a mixture of a metal or ametal salt with an acid, or a mixture of a metal or a metal salt withhydroxide, or sulfide of an alkali metal or ammonium, as a reducingagent. In case of using a method of catalytic reduction (1), as to thesolvent, water, acetic acid, an alcohol such as methanol, ethanol,isopropanol or the like, a hydrocarbon such as hexane, cyclohexane orthe like, an ether such as diethylene glycol dimethyl ether, dioxane,tetrahydrofuran, diethyl ether or the like, an ester such as ethylacetate, methyl acetate or the like, an aprotic polar solvent such asdimethylformamide can be exemplified. As to the catalyst, palladium,palladium black, palladium-carbon, platinum, platinum oxide, copperchromite, Raney nickel or the like can be used. The amount of thecatalyst to be used may be of 0.02 to 1.00 times the weight of thecompound (24). The reduction is carried out at -20° to 100° C.,preferably 0° to 50° C., under 1 to 10 atmospheric pressure of hydrogenand the reduction is generally completed in about 0.5 to 10 hours. Thecatalytic reduction can advantageously be carried out by adding a basicsubstance such as sodium hydroxide or potassium hydroxide or the like.On the other hand, in case of using a method (2), a mixture of iron,zinc, tin or stannic chloride with a mineral acid such as hydrochloricacid or sulfuric acid, or a mixture of iron, ferrous sulfate, zinc ortin with an alkali metal hydroxide such as sodium hydroxide, a sulfidesuch as ammonium sulfide, ammonia water, or an ammonium salt such asammonium chloride, can be used as the reducing agent. As to the solventto be used, water, acetic acid, methanol, ethanol, dioxane or the likecan be exemplified. The reduction reaction condition can suitably beselected depend on the catalyst to be used, and generally the reactioncan be carried out at -50° to 100° C., and is completed within 0.5 to 10hours. For example, in case of using stannous chloride with hydrochloricacid used as the reducing agent, the reaction can advantageously becarried out at about -20° to 50° C. The amount of the reducing agent canbe at least an equimolar quantity, generally an equimolar to 3 times themolar quantity to the starting material. In the above-mentionedreaction, the nitro group of compound of the general formula (24) isfist changed to amino group to form a compound represented by thegeneral formula (24'): ##STR24## wherein R⁷ and X⁴ are the same asdefined previously. Then this compound (24') is converted into acarbostyril compound (25) by ring closing reaction. In the reaction ofreducing a compound (24) to a compound (24'), the carbonyl group in thecompound (24) is not affected under the condition of reduction (2),however under the condition of reduction (1), the carbonyl group issometimes converted into methylene group. By selecting the reducingconditions suitably, the carbonyl group can be kept as it is. Thereaction of a compound of the general formula (25) with a compound ofthe general formula (12) can be carried out by a procedure similar tothat described in the reaction of a compound of the general formula(1-d) with a compound of the general formula (12) as mentionedpreviously. ##STR25## wherein R⁷, X³ and X⁴ are the same as definedpreviously.

The nitration of a compound (23) can be carried out under conditionssimilar to the nitration of a compound (23) in reaction processformula-10a, except the reaction temperature which may suitably byselected. The reaction can advantageously be carried out at atemperature within -10° C. to a room temperature.

The reaction for obtaining a compound of the general formula (2a) byreducing and ring closing a compound of the general formula (24a) can becarried out under conditions similar to the reaction for obtaining acompound of the general formula (26) as described in reaction processformula-10a. In the above-mentioned reaction, the nitro group of acompound (24a) is first changed to an amino group to form a compound ofthe general formula (24a'), ##STR26## wherein R⁷ is the same as definedpreviously.

A compound of the general formula (24a') is then converted into acarbostyril compound of the general formula (2a) by ring closingreaction. ##STR27## wherein R⁷ and X³ are the same as defined above; R⁸is a lower alkyl group.

The reaction of a compound of the general formula (27) with a compoundof the general formula (28) can be carried out under conditions similarto the reaction of a compound (4) with a compound (5), wherein thecompound (5) is a carboxylic acid halide, except the ratio of theamounts of the reactants. The reaction can be carried out even in theabsence of a basic compound, and the ratio of the amount of a compoundof the general formula (27) to the amount of a compound of the generalformula (28) may be at least in an equimolar quantity, preferably 1 to 5times the molar quantity to the latter. The cyclization reaction of acompound of the general formula (29) can be carried out in the presenceof an acid in the absence or presence of a suitable solvent. As to theacid to be used is not specifically restricted and any inorganic acid ororganic acid can be used, concretely, an inorganic acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, a Lewis acid such asaluminium chloride, boron trifluoride, titanium tetrachloride or thelike, an organic acid such as formic acid, acetic acid, ethanesulfonicacid, p-toluenesulfonic acid can be exemplified. Among these acids,hydrochloric acid, hydrobromic acid, sulfuric acid are specificallypreferable. The amount of the acid to be used is not specificallyrestricted, the amount can be selected from a wide range, generally atleast an equivalent weight, preferably 10 to 50 parts by weight of theacid may be used to the weight of a compound of the general formula(29). As to the solvent, any inert solvent can be used, for example,water, a lower alcohol such as methanol, ethanol, propanol or the like,an ether such as dioxane, tetrahydrofuran or the like, an aromatichydrocarbon such as benzene, toluene or the like, a halogeneratedhydrocarbon such as methylene chloride, chloroform, carbon tetrachlorideor the like, acetone, dimethyl sulfoxide, dimethylformamide,hexamethylphosphoric triamide or the like can be exemplified. Amongthese solvents, a water-soluble solvent such as a lower alcohol, anether, acetone, dimethyl sulfoxide, dimethylformamide,hexamethylphosphoric triamide or the like are preferable. This reactionis carried out generally at 0° to 100° C., preferably at roomtemperature to 60° C., and the reaction is generally completed in 5minutes to 6 hours. ##STR28## wherein R¹, R² and R³ are the same asdefined previously.

The reduction of a compound of the general formula (1g) or (2d) can becarried out by applying a condition of usual catalytic reduction. As tothe catalyst used in this reduction, a metal catalyst such as palladium,palladium-carbon, platinum, Raney nickel or the like can be exemplified.Said metal catalyst may be used in an usual catalytic amount. As to thesolvent, water, methanol, ethanol, isopropanol, dioxane,tetrahydrofuran, hexane, cyclohexane, ethyl acetate or the like can beexemplified or a mixture of the exemplified solvents can also be used.The reduction can be carried out at a normal pressure or under apressurized condition, generally the reduction may be carried out at anormal pressure to 20 kg/cm², preferably at a normal pressure to 10kg/cm². The reduction may be carried out generally at 0° to 150° C.,preferably at a room temperature to 100° C.

The dehydrogeneration of a compound of the general formula (1f) or (2c)can be carried out in a suitable solvent. As to the oxidizing agent tobe used in this reaction, a benzoquinone such as2,3-dichloro-5,6-dicyanobenzoquinone, chloranil(2,3,5,6-tetrachlorobenzoquinone) or the like, a halogenating agent suchas N-bromosuccinimide, N-chlorosuccinimide or the like, adehydrogenating catalyst such as selenium dioxide, palladium-carbon,palladium black, palladium oxide, Raney nickel or the like can beexemplified. There is not any specific restriction to the amount of theoxidizing agent and the amount can be selected from a wide range,generally an equimolar quantity to 5 times the molar quantity,preferably 1 to 2 times the moar quantity of the oxidizing agent can beused to the compound of the general formula (1f) or (2c). In case ofusing the dehydrogenating catalyst, generally an usual excess amount maybe used. As to the solvent to be used in this reaction, an ether such asdioxane, tetrahydrofuran, methoxyethanol, dimethoxyethane or the like,an aromatic hydrocarbon such as benzene, toluene, xylene, cummene or thelike, a halogenated hydrocarbon such as dichloromethane, dichloroethane,chloroform, carbon tetrachloride or the like, an alcohol such asbutanol, amylalcohol, hexanol or the like, a protic polar solvent suchas acetic acid or the like an aprotic polar solvent such asdimethylformamide, dimethyl sulfoxide, hexamethylphosphoric trimamide orthe like can be exemplified. The reaction can be carried out at a roomtemperature to 300° C., preferably a room temperature to 200° C., andthe reaction is generally completed in 1 to 40 hours.

Among the compounds represented by the general formula (1) of thepresent invention, those having hydrogen atom for the symbol R¹ furtherhaving double bond in the carbon-carbon bond between 3- and 4-positionsin the carbostyril skeleton capable of existing in tautomeric system inthe form of lactim-lactam as shown in the following reaction processformula-13. ##STR29##

Among the compounds represented by the general formula (1) of thepresent invention, compounds having basic group can easily be convertedinto their acid addition salts by reacting with pharmaceuticallyacceptable acids. The examples of such acids including inorganic acidssuch as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromicacid or the like; organic acids such as oxalic acid, maleic acid,fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid orthe like.

The desired compounds as prepared by the procedures in theabove-mentioned various reaction process formulas can easily be isolatedand purified by usual separation means such as solvent extraction,dilution, recrystallization, column chromatography, preparativethin-layer chromatography.

Carbostyril derivatives of the present invetion also including theiroptical isomers.

Carbostyril derivatives of the general formula (1) can be used in theform of pharmaceutical composition together with usual pharmaceuticallyacceptable carriers. The examples of the carriers which are useddepending on the desired form of pharmaceutical composition, includingdiluents or excipients such as fillers, diluents, binders, wettingagents, disintegrators, surface active agents, lubricants.

No particular restriction is made to the administration unit forms andthe compositions can be selected in any desired unit form, includingtablets, pills, powders, liquors, suspensions, emulsions, granules,capsules, suppositories, injections (solutions and suspensions) andointments.

For the purpose of to shape in the form of tablets, carriers which areknown in this field can also be used, for example excipients such aslactose, sucrose, sodium chloride, glucose, ures, starch, calciumcarbonate, caolin, crystalline cellulose, silici acid; binding agentssuch as water, ethanol, propanol, simple syrup, solution of glucose,starch solution, gelatin solution, carboxymethylcellulose, shelac,methylcellulose, calcium phosphate and polyvinylpyrrolidone;desintegrators such as dried starch, sodium alginate, agar-agar powder,laminalia powder, sodium hydrogencarbonate, calcium carbonate, Tweens,sodium laurylsulfate, monoglyceride of stearic acid, starch, lactose;desintegration inhibitors such as sucrose, stearin, coconut butter,hydrogenated oil; adsorption accelerators such as quarternary ammoniumbase, sodium laurylsulfate; wetting agents such as glycerin, starch;adsorbing agents such as starch, lactose, caoline, bentonite, colloidalsilicic acid; lubricants such as purified talc, stearic acid salt, boricacid powder, polyethylene glycol. In case of preparing tablets, they canbe further coated with the usual coating materials to make sugar coatedtablets, gelatin film coated tablets, tablets coated with entericcoatings, tablets coated with films or double layered tablets andmultilayered tablets.

For the purpose of to shape in the form of pills, carriers which isknown and widely used in this field can also be used, for example,excipients such as glucose, lactose, starch, coconut butter,hydrogenated oils, caolin and talc; binders such as powdered gumiababicum, powdered Tragacanth, gelatin and ethanol; desintegrators suchas laminaria and agar-agar are included.

For the purpose of to shape in the form of suppositories, carriers whichare known and widely used in this field can also be used, for example,polyethylene glycols, coconut butter, higher alcohols, esters of higheralcohols, gelatin and semi-synthesized glycerides are included.

For the purpose of to make in the form of injection preparations,solutions and suspensions are sterilized and are preferably isotonic toblood. In making injection preparations, every carriers which arecommonly used in this field can also be used, for example, water, ethyl,alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyxylatedisostearyl alcohol, polyoxyethylene sorbitol, sorbitane esters areincluded. In these instances, adequate amounts of sodium chloride,glucose or glycerin can be added to contain in the desired preparationsfor the purpose of to have them isotonic. Furthermore, the usualdissolving agents, buffers, analgesic agents, preservitives can be addedas well as coloring materials, perfumes, seasoning agents, sweeteningagents and other medicines can also be added into the desiredpreparations, if necessary.

The amount of a compound of the general formula (1) to be contained inthe pharmaceutical preparation (cardiotonic composition) is notspecifically restricted and it can suitably be selected from a widerange, and usually 1 to 70% by weight, preferably 1 to 30% by weight ofthe whole composition is preferable.

The above-mentioned cardiotonic composition can be used in various formsdepending on the purpose without any restriction, thus the compositionis administered in a suitable method according to the forms of thepreparation, the age of the patient, the distinction of sex, thecondition of the symptoms and other factors. For example, tablets,pills, solutions, suspensions, emulsions, granules and capsuled areadministered orally; and injection preparations are administeredintravenously singly or are mixed with injection transfusions such asglucose solutions and amino acids solution; if necessary the injectionpreparations are administered singly intramuscularly, intracutaneously,subcutaneously or intraperitoneally; suppositories are administered intorectum.

The dosage of the present cardiotonic composition is suitably selectedaccording to the usage, the age of the patient, the distinction of sex,the condition of the symptoms and other factors, generally 0.01 to 10mg/kg of body weight/day of a compound of the general formula (1) as theactive ingredient may be administered, and 0.1 to 200 mg of the activeingredient may be contained in the administration unit form.

Examples of cardiotonic composition containing carbostyril derivative ofthe present invention are shown as follows:

Example of preparation of tablets-1

By using an usual procedure, tablets having the following formulationwere prepared.

    ______________________________________                                        6-[4-(3,4-Dimethoxybenzyl)-                                                                           5      mg                                             1-piperazinylcarbonyl)]-3,4-                                                  dihydrocarbostyril                                                            Starch                  132    mg                                             Magnesium stearate      18     mg                                             Lactose                 45     mg                                             Total                   200    mg                                             ______________________________________                                    

Example of preparation of tablets-2

By using an usual procedure, tablets having the following formulationwere prepared.

    ______________________________________                                        6-[4-(2-Phenoxyethyl)-  10     mg                                             1-piperazinylcarbonyl]-3,4-                                                   dihydrocarbostyril                                                            Starch                  127    mg                                             Magnesium stearate      18     mg                                             Lactose                 45     mg                                             Total                   200    mg                                             ______________________________________                                    

Example of preparation of tablets-3

By using an usual procedure, tablets having the following formulationwere prepared.

    ______________________________________                                        6-(4-Isobutyryl-1-piperazinyl-                                                                         5      mg                                            carbonyl)-3,4-dihydrocarbostyril                                              monohydrochloride                                                             Starch                   132    mg                                            Magnesium stearate       18     mg                                            Lactose                  45     mg                                            Total                    200    mg                                            ______________________________________                                    

Example of preparation of injections

    ______________________________________                                        6-(4-Benzyl-1-piperazinyl-                                                                             500    mg                                            carbonyl)-3,4-dihydrocarbostyril                                              Polyethylene glycol      0.3    g                                             (Molecular weight: 4,000)                                                     Sodium chloride          0.9    g                                             Polyoxyethylene sorbitan monooleate                                                                    0.4    g                                             Sodium metabisulfite     0.1    g                                             Methyl p-hydroxybenzoate 0.18   g                                             Propyl p-hydroxybenzoate 0.02   g                                             Distilled water for injection                                                                          100    ml                                            ______________________________________                                    

Above prescribed methyl p-hydroxybenzoate, propyl p-hydroxybenzoate,sodium chloride and sodium metabisulfite were dissolved in about a halfthe quantity of distilled water at 80° C. under stirring. The obtainedsolution is cooled to 40° C., and6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril, polyethyleneglycol and polyoxyethylene sorbitan monooleate are dissolved in thatorder in said solution. This solution was further added with distilledwater for injection to the final regulated volume and then sterilized bysterile filtration with a suitable filter paper. One milliliter each ofthe obtained solution was filled in an ampoule separately to makeinjection preparations.

Pharmacological activities of compounds of the general formula (1) ofthe present invention were conducted by test methods as explained belowwith the following results.

    ______________________________________                                        Compounds used in the tests are as follows:                                   Compound                                                                      No.     Name of the compound                                                  ______________________________________                                         1      6-(l-Piperazinylcarbonyl)-3,4-dihydrocarbostyril                       2      6-[4-(2-Phenoxyethyl)-1-piperazinylcarbonyl]-                                 3,4-dihydrocarbostyril                                                 3      6-[4-(2-Cyanoethyl)-1-piperazinylcarbonyl]-                                   3,4-dihydrocarbostyril monohydrochloride                               4      6-(4-Methyl-1-piperazinylcarbonyl)-3,4-                                       dihydrocarbostyril                                                     5      6-[4-(3,4-Dimethoxybenzoyl)-1-piperazinyl-                                    carbonyl]-3,4-dihydrocarbostyril                                       6      6-[4-(4-Cyanobenzoyl)-1-piperazinylcarbonyl]-                                 3,4-dihydrocarbostyril                                                 7      6-[4-(4-Methoxybenzoyl)-1-piperazinylcarbonyl-                                3,4-dihydrocarbostyril                                                 8      6-[4-(3-Chlorobenzoyl)-1-piperazinylcarbonyl]-                                3,4-dihydrocarbostyril                                                 9      6-[4-(3,4-Dichlorobenzoyl)-1-piperazinyl-                                     carbonyl]-3,4-dihydrocarbostyril                                      10      6-[4-(4-Nitrobenzoyl)-1-piperazinylcarbonyl]-                                 3,4-dihydrocarbostyril                                                11      6-[4-(4-Methylbenzoyl)-1-piperazinylcarbonyl]-                                3,4-dihydrocarbostyril                                                12      6-(4-Ethoxycarbonyl-1-piperazinylcarbonyl)-                                   3,4-dihydrocarbostyril                                                13      6-(4-Furoyl-1-piperazinylcarbonyl)-3,4-                                       dihydrocarbostyril                                                    14      6-(4-Benzyl-1-piperazinylcarbonyl)-3,4-                                       dihydrocarbostyril monohydrochloride                                  15      6-[4-(4-Methylbenzyl)-1-piperazinylcarbonyl]-                                 3,4-dihydrocarbostyril                                                16      6-[4-(4-Methoxybenzyl)-1-piperazinylcarbonyl]-                                3,4-dihydrocarbostril monohydrochloride                               17      6-[4-(4-Chlorobenzyl)-1-piperazinylcarbonyl]-                                 3,4-dihydrocarbostyril monohydrochloride                              18      6-[4-(3,4-Dimethoxybenzyl)-1-piperazinyl-                                     carbonyl]-3,4-dihydrocarbostyril monohydrochloride                    19      6-[4-(4-Nitrobenzyl)-1-piperazinylcarbonyl-                                   3,4-dihydrocarbostyril monohydrochloride                              20      6-[N--Methyl-N--(4-methoxybenzyl)carbamoyl]-                                  3,4-dihydrocarbostyril                                                21      6-[N--Methyl-N--(3,4-methylenedioxybenzyl)-                                   carbamoyl]-3,4-dihydrocarbostyril                                     22      6-[N--Methyl-N--  (4-chlorobenzyl)carbamoyl]-                                 3,4-dihydrocarbostyril                                                23      Amrinone: [3-Amino-5-(4-pyridinyl-)-2-(H)-                                    pyridinone]                                                           24      6-[4-(2-Phenoxyethyl)-1-piperazinylcarbonyl]-                                 carbostyril monohydrochloride                                         25      6-[4-(3-Phenylpropyl)-1-piperazinylcarbonyl]-                                 carbostyril monohydrochloride                                         26      6-[4-(2-Benzoylethyl)-1-piperazinylcarbonyl]-                                 3,4-dihydrocarbostyril                                                27      Dobutamine: 3,4-Dihydroxy-N--[3-(4-hydroxy-                                   phenyl)-1-methylpropyl]-β-phenylethylamine                       28      6-[4-(4-Chlorobenzyl)-1-piperazinylcarbonyl]-                                 carbostyril monohydrochloride                                         29      6-[4-(3-Benzoylpropyl)-1-piperazinylcarbonyl]-                                3,4-dihydrocarbostyril monohydrochloride                                      1/2-hydrate                                                           30      6-[4-(4-Hydroxybenzoyl)methyl-1-piperazinyl-                                  carbonyl]-3,4-dihydrocarbostyril monohydrochloride                            1/2-hydrate                                                           31      6-(4-Propyl-1-piperazinylcarbonyl)-3,4-                                       dihydrocarbostyril                                                    32      6-[4-(3-Chlorobenzoyl)methyl-1-piperazinyl-                                   carbonyl]-3,4-dihydrocarbostyril monohydrochloride                            1/2-hydrate                                                           33      6-(4-Isopentyl-1-piperazinylcarbonyl)-3,4-                                    dihydrocarbostyril                                                    34      6-[4-(4-Methylthiobenzyl)-1-piperazinylcarbonyl]-                             3,4-dihydrocarbostyril monohydrochloride                              35      6-[4-(3,4,5-Trimethoxybenzyl)-1-piperazinyl-                                  carbonyl]-3,4-dihydrocarbostyril monohydrochloride                    36      6-[4-(4-Aminobenzyl)-1-piperazinylcarbonyl]-                                  3,4-dihydrocarbostyril                                                37      6-[4-(4-Acetylaminobenzyl)-1-piperazinyl-                                     carbonyl]-3,4-dihydrocarbostyril monohydro-                                   chloride 3/2-hydrate                                                  38      6-(4-Isobutyl-1-piperazinylcarbonyl)carbostyril                               monohydrochloride 1/2-hydrate                                         39      6-[4-(4-Methylbenzoylmethyl)-1-piperazinyl-                                   carbonyl]-3,4-dihydrocarbostyril monohydro-                                   chloride                                                              40      6-(4-Cyclohexylmethyl-1-piperazinylcarbonyl)-                                 3,4-dihydrocarbostyril monohydrochloride                              41      6-(4-Isobutyl-1-piperazinylcarbonyl)-3,4-                                     dihydrocarbostyril monohydrochloride                                  42      6-(4-Propargyl-1-piperazinylcarbonyl)-3,4-                                    dihydrocarbostyril monohydrochloride                                  43      6-[4-(4-Methoxybenzoyl)methyl-1-piperazinyl-                                  carbonyl]-3,4-dihydrocarbostyril monohydro-                                   chloride                                                              44      6-(4-n-Hexyl-1-piperazinylcarbonyl)-3,4-                                      dihydrocarbostyril monohydrochloride                                  45      1-Methyl-6-(4-benzyl-1-piperazinylcarbonyl)-                                  3,4-dihydrocarbostyril                                                46      6-(4-Allyl-1-piperazinylcarbonyl)-3,4-dihydro-                                carbostyril monohydrochloride                                         47      1-Propargyl-6-[4-(2-phenoxyethyl)-1-piperazinyl-                              carbonyl]-3,4-dihydrocarbostyril monohydro-                                   chloride                                                              48      1-Benzyl-6-[4-(2-phenoxyethyl)-1-piperazinyl-                                 carbonyl]-3,4-dihydrocarbostyril monohydro-                                   chloride                                                              49      1-Allyl-6-[4-(2-phenoxyethyl)-1-piperazinyl-                                  carbonyl]-3,4-dihydrocarbostyril monohydro-                                   chloride                                                              50      6-[4-(2-Hydroxyethyl)-1-piperazinylcarbonyl]-                                 3,4-dihydrocarbostyril dihydrate                                      51      6-(1-Piperidylcarbonyl)-3,4-dihydrocarbostyril                        52      6-(4-Methyl-1-piperidylcarbonyl)-3,4-dihydro-                                 carbostyril                                                           53      6-(4-Benzyl-1-piperidylcarbonyl)-3,4-                                         dihydrocarbostyril 1/2-hydrate                                        54      6-(1-Pyrrolidylcarbonyl)-3,4-dihydrocarbostyril                       55      6-{4-[3-(2-Chlorophenoxy)propyl]-1-piperazinyl-                               carbonyl}-3,4-dihydrocarbostyril monohydro-                                   chloride                                                              56      6-{4-[2-(4-Methoxyphenoxy)ethyl]-1-piperazinyl-                               carbonyl}-3,4-dihydrocarbostyril monohydro-                                   chloride                                                              57      6-{4-[2-(3,4-Methylenedioxyphenoxy)ethyl]-1-                                  piperzinylcarbonyl}-3,4-dihydrocarbostyril                                    monohydrochloride                                                     58      6-[4-(5-Benzoylpentyl)-1-piperazinylcarbonyl]-                                3,4-dihydrocarbostyril monohydrochloride                                      monohydrate                                                           59      6-{4-[3-(3,4-Dimethoxybenzoyl)propyl]-1-                                      piperazinylcarbonyl}-3,4-dihydrocarbostyril                                   monohydrochloride 1/2-hydrate                                         60      6-[4-(3-Chlorocinnamoyl)-piperazinylcarbonyl]-                                3,4-dihydrocarbostyril 1/4-hydrate                                    61      6-[4-(3,4,5-Trimethoxycinnamoyl)-1-piperazinyl-                               carbonyl]-3,4-dihydrocarbostyril                                      62      6-[4-(2-Acetyloxypropyl)-1-piperazinylcarbonyl]-                              3,4-dihydrocarbostyril monohydrochloride                                      1/2-hydrate                                                           63      5-(4-Isobutyl-1-piperazinylcarbonyl)carbostyril                               monohydrochloride 1/2-hydrate                                         64      7-(4-Benzyl-1-piperazinylcarbonyl)-3,4-                                       dihydrocarbostyril monohydrochloride                                  65      8-[4-(3-Phenylpropyl)-1-piperazinylcarbonyl]-                                 3,4-dihydrocarbostyril monohydrochloride                              66      6-(4-Ethoxycarbonylmethyl-1-piperazinyl-                                      carbonyl)-3,4-dihydrocarbostyril monohydro-                                   chloride                                                              67      6-[4-(2-Ethoxycarbonylethyl)-1-piperazinyl-                                   carbonyl]-3,4-dihydrocarbostyril                                      68      6-[4-(2-Chloropropyl)-1-piperazinylcarbonyl]-                                 3,4-dihydrocarbostyril monohydrochloride                              69      6-(4-Methanesulfonyl-1-piperazinylcarbonyl)-                                  3,4-dihydrocarbostyril                                                70      6-(4-Formyl-1-piperazinylcarbonyl)-3,4-                                       dihydrocarbostyril                                                    71      6-{4-[2-(4-Acetylaminobenzoyl)ethyl]-1-                                       piperazinylcarbonyl}-3,4-dihydrocarbostyril                           72      6-[4-(4-Methoxyphenylacetyl)-1-piperazinyl-                                   carbonyl]-3,4-dihydrocarbostyril                                      ______________________________________                                    

Pharmacological test-1

Adult mongrel dogs of either sex, weighing 8-13 kg, were anesthetizedwith sodium pentobarbital at a rate of 30 mg/kg by intravenousadministration. After another intraveneous administration of sodiumheparin at a rate of 1,000 U/kg, the test dog was sacrifieced by bloodletting. The heart of the dog was excised and immediately plunged intoLocke's solution, then the right coronary artery was cannulated to theatrionector artery and the right atrium was carefully isolated.

Next, the donor adult mongrel dogs of either sex, weighing 18-27 kg,were anesthetized with sodium pentobarbital at a rate of 30 mg/kg byintraveneous administration, and further treated with intraveneousadministration of sodium heparin at a rate of 1,000 U/kg.

The above-mentioned right atrium was perfused with the blood conductedfrom the carotid artery of the donor dog by aid of Peristaric pump. Theperfusion pressure was maintained at 100 mm-Hg constantly. The movementof the right atrium was measured through a force-displacement transducerunder a static tension of 2 g. The amount of blood flown in the coronaryarteries was measured by electromagnetic flow meter. All the data wererecorded on an ink-writing recorder. [The method of this test isreported in an article written by Chiba et al., "Japan Journal ofPharmacology, 25, 433-439, (1975), Naunyn-Schmiedberg's Arch.Pharmacology, 289, 315-325, (1975).]

A solution containing a compound to be tested was injected into theartery through the rubber tube connected close to the cannula, in anamount of 10-30 ul.

Positive inotropic effect of the compound to be tested is expressed as apercentage of the developed tension before and after the injection ofthe compound. The effect of the compound on blood flow in coronaryartery is expressed as an absolute value (ml/minute) measured frombefore the injection of the compound.

The results are shown in Tables 1 and 2 below.

                  TABLE 1                                                         ______________________________________                                                          Change of   Change of blood                                 Compound          atrial muscle                                                                             flow in coronary                                No.     Dosage    contriction artery                                          ______________________________________                                         1      1 u mol   11.7%       1 ml/minute                                      2      1 u mol   165.0       4                                                3      300 n mol 24.3        --                                               4      1 u mol   65.8        1.5                                              5      1 u mol   63.2        --                                               6      300 n mol --          1                                                7      300 n mol 21.4        --                                               8      300 n mol 20.5        --                                               9      300 n mol 24          --                                              10      100 n mol 10.5        --                                              11      300 n mol 23.2        2                                               12      1 u mol   125.0       2.5                                             13      1 u mol   80.0        1                                               14      1 u mol   145.5       1.5                                             15      1 u mol   96.2        1.5                                             16      1 u mol   132.0       2.5                                             17      1 u mol   68.0        2                                               18      1 u mol   114.6       3                                               19      1 u mol   94.6        1.5                                               23(a) 1 u mol   57.5        --                                              ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                                          Change of   Change of blood                                 Compound          atrial muscle                                                                             flow in coronary                                No.     Dosage    contriction artery                                          ______________________________________                                        20      300 n mol  42.2%      2.0 ml/minute                                   21      300 n mol 42.0        1.5                                             22      300 n mol 53.5        1.5                                               23(b)  1 u mol  58.8        --                                              ______________________________________                                    

Pharmacological test-2

Mongrel dogs of either sex, weighing 9-15 kg, were anesthetized withsodium pentobarbital initially in a dosage of 30 mg/kg intravenously andsubsequently at a rate of 4 mg/kg/hr intravenously by using an infusionpump. The animals were respired with room air in a tidal volume of 20ml/kg at a rate of 18 beats/minute by using respirator. The chest wasopened by a midline incision and the heart was suspended in thepericardial cradle.

The contractile force of the myocardium was measured by means of aWalton-Brodie type strain-gauge arch sutured onto the left ventricle.Systemic blood pressure was measured from the left femoral artery by apressure transducer. All recordings were made on a chart by the use of arectilinear recorder.

A compound to be tested was injected into the left femoral vein.

The inotropic effects of the compounds are expressed as a percentage ofthe developed tension before the injection on the compound.

The effect of the compound on blood pressure (mm-Hg) is expressed as adifference between the values before and after the injection of thecompound.

The results are shown in Table 3 below.

                  TABLE 3                                                         ______________________________________                                                         Change of    Blood pressure                                  Compound                                                                              Dosage   contriction of                                                                             (mm-Hg)                                         No.     (mg/kg)  left ventricle (%)                                                                         Diostasis                                                                            Systole                                  ______________________________________                                        24      1        74.4         -52    -34                                      25      1        29.6         -42    -24                                      26      1        17.9         -20    -18                                      14      1        40.5         -36    -22                                       2      1        20.0         -38    -44                                      27        0.01   83.9         -30     32                                      ______________________________________                                    

Pharmacological test-3

Adult mongrel dogs of either sex, weighing 8-13 kg, were anesthetizedwith sodium pentobarbital at a rate of 30 mg/kg by intraveneousadministration. After another intraveneous administration of sodiumheparin at a rate of 1,000 U/kg, the test dog was sacrificed by bloodletting. The heart of the dog was excised and the preparation wasessentially consisting from the anterior papillary muscle excisedtogether with the ventricular septum and was set up in cold Tyrode'ssolution. The preparation was placed in a glass water jacket maintainedat about 38° C. and cross-circulated through the cannulated anteriorseptal artery with blood from a donor dog at a constant pressure of 100mm-Hg. The dogs used as donors were weighing 18-27 kg, and wereanesthetized with pentobarbital sodium at a rate of 30 mg/kg byintraveneous administration, and further treated with intraveneousadministration of sodium heparin at a rate of 1,000 U/kg. The papillarymuscle was driven with rectangular pulse about 1.5 times the thresholdvoltage (0.5-3 volts) and 5 seconds duration at a fixed rate of 120beats/minute through bipolar pacing electrodes. Tension developed by thepapillary muscle was measured by a strain-gauge transducer. The musclewas loaded with a weight of about 1.5 g. Blood flow through the anteriorseptal artery was measured by an electromagnetic flow meter. Recordingof developed tension and blood flow was made on charts with anink-writing rectigraph. [The details of this test method is reported inan article written by Endoh and Hashimoto, "American Journal ofPhysiology, 218, 1459-1463, (1970)".]

A compound to be tested was injected into the intra-arterially in anamount of 10-30 ul in 4 seconds.

The inotropic effects of the compounds are expressed as a percentage ofthe developed tension before the injection of the compound.

The effect of the compound of blood flow are expressed as a difference(ml/minute) of the values before and after the injection of thecompound.

The results are shown in Table 4 below.

                  TABLE 4                                                         ______________________________________                                                          Change of   Change of blood                                 Compound          arterial muscle                                                                           flow in coronary                                No.     Dosage    contriction artery                                          ______________________________________                                        50      1 u mol   8.0%        0.5 ml/minute                                   51      1 u mol   25.6        1.5                                             52      1 u mol   39.5        2.5                                             53      300 n mol 10.4        1.0                                             54      1 u mol   28.6        0.5                                             55      1 u mol   46.8        1.5                                             56      1 u mol   13.5        4                                               57      1 u mol   13.2        3.5                                             58      1 u mol   45.5        3.8                                             59      1 u mol   25.0        1.5                                             60      300 n mol 12.5        1.0                                             61      1 u mol   48.0        --                                              62      1 u mol   8.3         3.5                                             63      3 u mol   10          --                                              64      1 u mol   9.0         1.9                                             65      1 u mol   6.6         0.9                                             66      1 u mol   11.8        0.6                                             67      1 u mol   25.0        1.2                                             68      1 u mol   31.8        4.1                                             69      3 u mol   10          --                                              70      3 u mol   10          --                                              71      3 u mol   19.4        --                                              72      1 u mol   20.8        5.5                                               23(a) 1 u mol   54.8        --                                              ______________________________________                                    

The present invention will be illustrated more in specifically by way offollowing examples, in which the preparation of the compounds to be usedas the starting materials will be shown in Reference Examples and thepreparation of the objective compounds will be shown in Examples.

REFERENCE EXAMPLE 1

50 Grams of 6-(α-pyridiniumacetyl)-3,4-dihydrocarbostyril chloride and50 g of sodium hydroxide were suspended in 1 liter of water and thesuspension was stirred at 90° to 100° C. for 3 hours. After the reactionwas completed, a certain amount of concentrated hydrochloric acid wasadded to the reaction mixture so as to make the pH value of the mixtureto about pH 2 to precipitate crystals, then the crystals were collectedby filtration. Recrystallization from dimethylformamide to obtain 19.1 gof 6-carboxy-3,4-dihydrocarbostyril.

Melting point: over 300° C.

Light yellow powdery crystals.

REFERENCE EXAMPLE 2

10 Grams of 6-carboxy-3,4-dihydrocarbostyril and 6.0 g ofN-hydroxysuccinimide were suspended in 200 ml of dioxane. Then asolution of 12.4 g of dichlorohexylcarbodiimide in 50 ml of dioxane wasadded drop-wise of the suspension under ice-cooling with stirring. Thereaction mixture was heated at 90° C. for 4 hours. After the reactionwas completed, the reaction mixture was cooled to a room temperature,and the crystals being precipitated were removed by filtration and themother liquor was concentrated by distillation. The residue wasrecrystallized from dimethylformamide-ethanol to obtain 10.8 g ofsuccinimide 3,4-dihydrocarbostyril-6-carboxylate.

Melting point: 234.5°-236° C.

Colorless flake-like crystals.

REFERENCE EXAMPLE 3

15.1 Grams of 6-acetyl-3,4-dihydrocarbostyril was dissolved in 100 ml ofacetic acid and the solution was kept at a temperature of 35°-40° C. 10Milliliter of acetic acid containing 11.2 ml of bromine was addeddropwise to the above-mentioned solution for 3.5 hours under stirring.The reaction mixture was allowed to stand over night and the crystalsprecipitated in the mixture were collected by filtration and washed witha small amount of acetic acid. The crystals thus obtained were treatedwith activated carbon by using ethanol as a solvent. Recrystallized fromethanol to obtain 19.5 g of 6-dibromoacetyl-3,4-dihydrocarbostyril inthe form of light yellow needle-like crystals.

Melting point: 168°-169° C.

REFERENCE EXAMPLE 4

Into 250 ml of water, 26 g sodium hydroxide was dissolved, then at atemperature of 90°-100° C. and under stirring condition, 35 g of6-dibromoacetyl-3,4-dihydrocarbostyril was added thereinto and reactedfor 3 hours. After the reaction was completed, the reaction mixture wascooled and insoluble matters formed in the mixture were removed byfiltration. The mother liquor was acidified with concentratedhydrochloric acid and the crystals precipitated were collected byfiltration and washed with water. The crystals thus obtained wererecrystallized from ethanol twice to obtain 10.5 g of6-carboxy-3,4-dihydrocarbostyril in the form of light yellow amorphouscrystals.

Melting point: 324.5°-327° C. (decomposed)

REFERENCE EXAMPLE 5

60 Grams of 6-(α-chloroacetyl)carbostyril was suspended in 0.5 kg ofpyridine and stirred at 80°-90° C. for 2 hours, then the suspension wasstirred under ice-cooling for 1 hour. The crystals thus precipitatedwere collected by filtration and recrystallized from methanol to obtain70 g of 6-(α-pyridiniumacetyl)carbostyril chloride 1/2-hydrate in theform of colorless needle-like crystals.

Melting point: over 300° C.

REFERENCE EXAMPLE 6

69.7 Grams of 6-(α-pyridiniumacetyl)carbostyril chloride and 65 g ofsodium hydroxide were dissolved in 0.6 liter of water and stirred at atemperature of 60°-70° C. for 3 hours. Under the ice-cooled condition,to the reaction mixture was added concentrated hydrochloric acid so asto adjust the pH of the reaction mixture to about pH 2. Precipitatedcrystals were collected by filtration and recrystallized fromdimethylformamide to obtain 41.4 g of 6-carboxycarbostyril.

Light brown powdery crystals.

Melting point: over 300° C.

REFERENCE EXAMPLE 7

100 Grams of m-aminobenzoic acid was suspended in 1 liter of diethylether, and at a room temperature with stirring 44.6 g of β-ethoxyacrylicchloride was added dropwise. Then the reaction mixture was heated at 40°C. for 5 hours. After the reaction was completed, the precipitatedmatter was collected by filtration and washed with water three times,and dried, and recrystallized from methanol to obtain 60 g ofm-carboxy-N-(β-ethoxyacryloyl)aniline.

Colorless cotton-like crystals.

Melting point: 200.5°-202° C.

REFERENCE EXAMPLE 8

8 Grams of m-carboxy-N-(β-ethoxyacryloyl)aniline was added in 80 ml ofconcentrated sulfuric acid and stirred at a room temperature for 2hours, then stirred at 50° C. for 1 hour. The reaction mixture waspoured into ice and the pH of the mixture was adjusted to pH 3-4 byadding 10 N-sodium hydroxide aqueous solution. The precipitated crystalswere collected by filtration and washed with water, recrystallized fromdimethylformamide to obtain 4.26 g of 5-carboxycarbostyril.

Light yellow powdery crystals.

Melting point: over 320° C.

NMR (DMSO): δ6.58 (d, J=9.5 Hz, 1H), 7.40-7.80 (m, 3H), 8.69 (d, J=9.5Hz, 1H)

REFERENCE EXAMPLE 9

A mixture of 50 g of methyl 3-phenylpropionate, 51.6 g of chloroacetylchloride and 250 ml of dichloromethane was cooled to 0° C. Then at 0° to10° C. with stirring, 122 g of aluminum chloride was added slowly,stirred at a room temperature for 2 hours and allowed to standovernight. The reaction mixture was poured into an ice-concentratedhydrochloric acid and extracted with chloroform, then the chloroformlayer was washed with water, dried and the chloroform was removed bydistillation to obtain the residue, then isopropyl ether was added tothe residue to effect crystallization. The crystals were collected byfiltration, and recrystallized from ethanol to obtain 53.4 g of methyl3-(4-chloroacetylphenyl)-propionate.

Colorless needle-like crystals.

Melting point: 90°-92° C.

REFERENCE EXAMPLE 10

36.26 Grams of methyl 3-(4-chloroacetylphenyl)-propionate was dissolvedin 300 ml of concentrated sulfuric acid, then 20.9 g of fuming nitricacid (d=1.52) was added dropwise under ice-cooled condition withstirring. The reaction mixture was stirred at a room temperature for 3hours then the reaction mixture was poured into ice-water and extractedwith chloroform. The chloroform layer was washed with water and dried,then chloroform was removed by distillation. The residue thus obtainedwas treated by a silica gel chromatography and crystallized by addingether. The crystals were collected by filtration and recrystallized frommethanol to obtain 26.7 g of methyl3-(4-carboxyl-2-nitrophenyl)-propionate.

Light yellow prism-like crystals.

Melting point: 120°-122° C.

REFERENCE EXAMPLE 11

5 Grams of methyl 3-(4-carboxy-2-nitrophenyl)-propionate, 8.87 ml of2.226 N-sodium hydroxide methanol solution, 100 ml of methanol and 1 gof 5%-palladiumcarbon (containing 50% of water) were mixed together andthe mixture was catalytically reduced at a normal temperature and undera normal pressure. The catalyst was removed by filtration and to themother liquor was added concentrated hydrochloric acid to adjust the pHto about 1 and the crystals formed were collected by filtration,recrystallized from methanol to obtain 3.62 g of7-carboxyl-3,4-dihydrocarbostyril.

Colorless needle-like crystals.

Melting point: over 320° C.

NMR (DMSO): δ=2.33-2.60 (m, 2H), 2.77-3.05 (m, 2H), 7.21 (d, J=8.5 Hz,1H), 7.38-7.53 (m, 2H), 10.15 (s, 1H)

REFERENCE EXAMPLE 12

To a solution containing 467 g of chloroacetyl chloride in 400 ml ofdichloromethane was added 735 g of aluminum chloride by way of one-thirdportion thereof in three times, at below 30° C., with stirring, then 200g of the carbostyril was added to the mixture at the same temperatureunder stirring. Then the reaction mixture was refluxed for 6 hours.After the reaction was completed, the reaction mixture was poured intoice-concentrated hydrochloric acid and the crystals formed werecollected by filtration, and washed with a hot methanol to obtain 153 gof 6-chloroacetylcarbostyril. The mother liquor was concentrated todryness and the residue was purified by a silica gel columncromatography. Recrystallized from methanol to obtain 35.41 g of8-chloroacetyl-carbostyril.

Light yellow needle-like crystals.

Melting point: 177.5°-179° C.

REFERENCE EXAMPLE 13

30 Grams of 8-chloroacetylcarbostyril was mixed with 300 ml of pyridineand stirred at 80°-90° C. for 2.5 hours under heating. Then the reactionmixture ice-cooled and crystals formed were collected by filtration andwashed with ether. Recrystallized from methanol to obtain 40.85 g of8-(α-pyridiniumacetyl)carbostyril chloride 1/2-hydrate.

Colorless needle-like crystals.

Melting point: 261.5°-264.0° C. (decomposed)

REFERENCE EXAMPLE 14

32 Grams of 8-(α-pyridiniumacetyl)carbostyril chloride, 300 ml of waterand 32 g of sodium hydroxide were mixted together and the mixture wasstirred at 80°-90° C. for 5 hours. The reaction mixture was treated withactivated carbon and to the mother liquor was added concentratedhydrochlorid acid to adjust the pH to about pH 3-4. The crystals formedwere collected by filtration, recrystallized from methanol-chloroform toobtain 20.17 g of 8-carboxycarbostyril.

Colorless needle-like crystals.

Melting point: over 320° C.

NMR (DMSO) δ=6.57 (d, J=9.5 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.94 (d,d,J=8.0 Hz, 1.5 Hz, 1H), 7.98 (d, J=9.5 Hz, 1H), 8.14 (d,d, J=8.0 Hz, 1.5Hz, 1H).

EXAMPLE 1

3.5 Grams of 6-carboxy-3,4-dihydrocarbostyril was dissolved in 30 ml ofdimethylformamide, then 2.4 g of triethylamine was added in thesolution. Under ice-cooled and stirring condition, 2.75 g of isobutylchloroformate was added dropwise into the reaction mixture and stirredfor 30 minutes. Then at a room temperature under stirring condition,3.19 g of N-methyl-N-(4-methoxy)-benzylamine was added dropwise to thereaction mixture and stirred for 5 hours. The reaction mixture wasconcentrated to dryness and extracted with chloroform and 1 N-sodiumhydroxide aqueous solution. The chloroform layer was washed with waterand after dried the chloroform layer, then ether was added to theresidue and the crystals thus formed were collected by filtration.Recrystallized from methanol to obtain 1.84 g of6-[N-methyl-N-(4-methoxybenzyl)carbomoyl]-3,4-dihydrocarbostyril in theform of colorless needle-like crystals.

Melting point: 144.5°-146.5° C.

EXAMPLE 2

By a method similar to that of Example 1, following compounds wereobtained:

6-[N-Methyl-N-(3,4-methylenedioxybenzyl)-carbamoyl]-3,4-dihydrocarbostyril

Colorless prism-like crystals (from ethanol)

Melting point: 170°-171° C.

6-[N-Methyl-N-(4-chlorobenzyl)carbamoyl]-3,4-dihydrocarbostyril

Colorless prism-like crystals (from ethanol)

Melting point: 171.5°-172.5° C.

EXAMPLE 3

127 Milligrams of succinimide 3,4-dihydrocarbostyril-6-carboxylate and39 mg of diethanolamine were dissolved in 2 ml of dimethylformamide andstirred at room temperature for 24 hours. Water was added to thereaction mixture and extracted with chloroform and the chloroform layerwas washed with water and a saurated sodium chloride aqueous solution inthis order. After drying the chloroform layer with anhydrous sodiumsulfate, the chloroform was removed by distillation under a reducedpressure, then acetone was added to the thus obtained residure tocrystallize the product. 48 Milligrams of6-(diethanolaminocarbonyl)-3,4-dihydrocarbostyril was obtained.

Melting point: 131°-134° C.

EXAMPLE 4

30 Milliliters of thionyl chloride was added to 2.2 g of6-(diethanolaminocarbonyl)-3,4-dihydrocarbostyril and the mixture wasstirred at a room temperature for 5 hours, then the reaction mixture wasconcentrated by distillation under a reduced pressure further 50 ml ofbenzene was added to the residue. The operation of concentration under areduced pressure was repeated three times, and6-{[di-(2-chloroethyl)]-aminocarbonyl}-3,4-dihydrocarbostyril wasobtained.

EXAMPLE 5

1.0 Gram of succenimide 3,4-dihydrocarbostyril-6-carboxylate and 0.37 gof morpholine were dissolved in 2 ml of dimethylformamide and stirred atroom temperature for 3 hours. Then water was added to the reactionmixture and extracted with chloroform, the chloroform layer was washedwith water and a saturated sodium chloride aqueous solution in thisorder. After drying the chloroform layer with anhydrous sodium sulfate,then chloroform was removed by distillation under a reduced pressure,then acetone was added to the thus obtained residue to crystallize theproduct. 150 Milligrams of 6-morpholinocarbonyl-3,4-dihydrocarbostyrilwas obtained.

Colorless granular crystals.

Melting point: 206°-207° C. (from ethanol).

EXAMPLE 6

127 Milligrams of succinimide 3,4-dihydrocarbostyril-6-carboxylate and93 mg of benzylpiperazine were dissolved in 2 ml of dimethylformaide andthe mixture was stirred at room temperature for 24 hours. Water wasadded to the reaction mixture and extracted with chloroform, thechloroform layer was washed with water and a saturated sodium chlorideaqueous solution. After drying the chloroform layer with anhydroussodium sulfate, chloroform was removed by distillation under a reducedpressure, then acetone was added to the thus obtained residue tocrystallize the product. Recrystallize from ethanol to obtain 130 mg of6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril.

Colorless needle-like crystals.

Melting point: 198°-200° C.

By a method similar to that of Example 6, following compounds ofExamples 7-108 were obtained:

EXAMPLE 7

6-[4-(2-Phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless needle-like crystals

Melting point: 271°-274° C. (decomposed)

EXAMPLE 8

6-[4-(2-Cyanoethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 240°-243° C. (decomposed)

EXAMPLE 9

6-(1-Piperazinylcarbonyl)-3,4-dihydrocarbostyril

Coloress flake-like crystals

Melting point: 211.5°-213° C.

EXAMPLE 10

6-[4-(3,4-Dimethoxybenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless granular crystals

Melting point: 240°-242° C. (decomposed)

EXAMPLE 11

6-[4-(4-Methylbenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 280°-283° C. (decomposed)

EXAMPLE 12

6-[4-(3,4-Dichlorobenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 284°-287° C. (decomposed)

EXAMPLE 13

6-[4-(4-Methoxybenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless granular crystals

Melting point: 262°-264° C. (decomposed)

EXAMPLE 14

6-[4-(4-Chlorobenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless needle-like crystals

Melting point: over 300° C.

EXAMPLE 15

6-[4-(4-Nitrobenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Light yellow granular crystals

Melting point: 268°-271° C. (decomposed)

EXAMPLE 16

6-[4-(3,4-Dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless granular crystals

Melting point: 238°-239.5° C.

EXAMPLE 17

6-[4-(4-Cyanobenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless needle-like crystals

Melting point: 294°-297° C.

EXAMPLE 18

6-[4-(4-Methoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 247°-249° C.

EXAMPLE 19

6-[4-(3-Chlorobenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 258.5°-260° C.

EXAMPLE 20

6-[4-(4-Bromobenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 265.5°-267.5° C.

EXAMPLE 21

6-[4-(3,4-Dichlorobenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless granular crystals

Melting point: 265°-267° C. (decomposed)

EXAMPLE 22

6-[4-(4-Nitrobenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Light yellow granular crystals

Melting point: 287°-289° C. (decomposed)

EXAMPLE 23

6-[4-(4-Methylbenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless flake-like crystals

Melting point: 262°-264.5° C.

EXAMPLE 24

6-(4-Carbamoylmethyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril

Colorless granular crystals

Melting point: 243.5°-244° C.

EXAMPLE 25

6-(4-Methyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydroiodide

Colorless powdery crystals

Melting point: 258°-259.5° C. (decomposed)

EXAMPLE 26

6-{4-[(4-Chlorophenyl)(phenyl)methyl]-1-1/2-hydrate

Colorless powdery crystals

Melting point: 199°-202° C. (decomposed)

EXAMPLE 27

6-[4-(p-Toluenesulfonyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless granular crystals

Melting point: 280°-282° C.

EXAMPLE 28

6-(4-Methanesulfonyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril

Colorless needle-like crystals

Melting point: 115°-116.5° C.

EXAMPLE 29

6-(4-Ethoxycarbonyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 180°-182° C.

EXAMPLE 30

6-(4-n-Hexyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 276°-280° C. (decomposed)

EXAMPLE 31

6-(4-Cyclohexylmethyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: over 300° C.

EXAMPLE 32

6-(4-Isobutyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 292°-293.5° C. (decomposed)

EXAMPLE 33

6-(4-Allyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 235°-238° C. (decomposed)

EXAMPLE 34

6-(4-Propargyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride

Colorless granular crystals

Melting point: 249°-251° C. (decomposed)

EXAMPLE 35

6-[4-(4-Methylthiobenzyl)-1-piperazinyl-carbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless granular crystals

Melting point: 264°-268° C. (decomposed)

EXAMPLE 36

6-[4-(3-Phenoxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 151°-153° C. (decomposed)

EXAMPLE 37

6-[4-(6-Phenoxyhexyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 254°-257° C. (decomposed)

EXAMPLE 38

6-[4-(2-Phenylethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 269°-272° C. (decomposed)

EXAMPLE 39

6-[4-(3-Phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 257°-259° C. (decomposed)

EXAMPLE 40

6-[4-(4-Aminobenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless granular crystals

Melting point: 213.5°-214.5° C.

EXAMPLE 41

6-[4-(4-Acetylaminobenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride 3/2-hydrate

Colorless powdery crystals

Melting point: 229°-231.5° C.

EXAMPLE 42

6-[4-(3,4,5-Trimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyri

Colorless powdery crystals

Melting point: 174°-176° C. (decomposed)

EXAMPLE 43

1-Methyl-6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril

Colorless flake-like crystals

Melting point: 145°-146° C.

EXAMPLE 44

1-Allyl-6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 239°-241° C.

EXAMPLE 45

1-Benzyl-6-[4-(2-phenoxyethyl)-1-piperazinyl-carbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 261°-264° C.

EXAMPLE 46

1-Propargyl-6-[4-(3-phenoxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Light yellow powdery crystals

Melting point: 137°-139° C. (decomposed)

EXAMPLE 47

6-[4-(2-Furoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 181°-183.5° C.

EXAMPLE 48

6-(4-Formyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 198°-201° C. (decomposed)

EXAMPLE 49

6-[4-(3,4,5-Trimethoxybenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless needle-like crystals

Melting point: 160°-164° C.

EXAMPLE 50

6-[4-(3,4-Methylenedioxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 251°-255° C. (decomposed)

EXAMPLE 51

6-[4-(2-Hydroxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrildihydrate

Colorless rhombic crystals

Melting point: 277°-279° C. (decomposed)

EXAMPLE 52

6-(4-Cyclohexyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril

Colorless needle-like crystals

Melting point: 170°-172.5° C.

EXAMPLE 53

6-[4-(3,4-Methylenedioxybenzyl)-1-piperazinyl-carbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 277°-279° C. (decomposed)

EXAMPLE 54

6-(1-Piperidylcarbonyl)-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 173°-174° C.

EXAMPLE 55

6-(4-Methyl-1-piperidylcarbonyl)-3,4-dihydrocarbostyril

Colorless rhombic crystals

Melting point: 212°-213.5° C.

EXAMPLE 56

6-(4-Benzyl-1-piperidylcarbonyl)-3,4-dihydrocarbostyril 1/2-hydrate

Colorless powdery crystals

Melting point: 235°-236.5° C.

EXAMPLE 57

6-(1-Pyrrolidylcarbonyl)-3,4-dihydrocarbostyril

Colorless needle-like crystals

Melting point: 200°-202° C.

EXAMPLE 58

6-[4-(4-Phenoxybutyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless granular crystals

Melting point: 250°-252° C.

EXAMPLE 59

6-{4-[3-(3-Chlorophenoxy)propyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride

Colorless needle-like crystals

Melting point: 254°-256.5° C. (decomposed)

EXAMPLE 60

6-4-[3-(2-Chlorophenoxy)propyl]-1-piperazinylcarbonyl-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 256°-258° C.

EXAMPLE 61

6-{4-[3-(4-Methylphenoxy)propyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 265°-266.5° C. (decomposed)

EXAMPLE 62

6-{4-[2-(4-Methoxyphenoxy)ethyl]-piperazinyl-carbonyl}-3,4-dihydrocarbostyrilmonohydrochloride

Colorless needle-like crystals

Melting point: 270°-272° C. (decomposed)

EXAMPLE 63

6-{4-[2-(3,4-Methylenedioxyphenoxy)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride

Colorless needle-like crystals

Melting point: 164°-166° C. (decomposed)

EXAMPLE 64

6-{4-[2-(3-Chorophenoxy)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 249°-251.5° C.

EXAMPLE 65

6-[4-(Benzoylmethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 212°-215° C.

EXAMPLE 66

6-{4-[(4-Methoxybenzoyl)methyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 266.5°-269° C. (decomposed)

EXAMPLE 67

6-{4-[(4-Chlorobenzoyl)methyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless flake-like crystals

Melting point: 242°-245° C. (decomposed)

EXAMPLE 68

6-{4-[(3-Chlorobenzoyl)methyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 143.5°-146° C. (decomposed)

EXAMPLE 69

6-{4-[(4-Methylbenzoyl)methyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 270°-272° C. (decomposed)

EXAMPLE 70

6-{4-[(4-Hydroxybenzoyl)methyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 162°-164° C.

EXAMPLE 71

6-[4-(2-Benzoylethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 205°-207° C. (decomposed)

EXAMPLE 72

6-[4-(3-Benzoylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless needle-like crystals

Melting point: 241°-242.5° C.

EXAMPLE 73

6-[4-(5-Benzoylpentyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride monohydrate

Colorless powdery crystals

Melting point: 239°-242° C.

EXAMPLE 74

6-{4-[3-(4-Ethylbenzoyl)propyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 230°-233° C. (decomposed)

EXAMPLE 75

6-{4-[3-(4-Chlorobenzoyl)propyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 238°-240° C.

EXAMPLE 76

6-{4-[3-(3,4-Dimethoxybenzoyl)propyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 225°-228° C.

EXAMPLE 77

6-{4-[2-(4-Methylbenzoyl)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyril

Colorless flake-like crystals

Melting point: 224.5°-226° C. (decomposed)

EXAMPLE 78

6-{4-[2-(4-Methoxybenzoyl)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride monohydrate

Colorless rhombic crystals

Melting point: 204°-205° C. (decomposed)

EXAMPLE b 79

6-{4-[2-(4-Acetylaminobenzoyl)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 207°-209° C. (decomposed)

EXAMPLE 80

6-[4-(3-Chlorocinnamoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril1/4-hydrate

Colorless granular crystals

Melting point: 239.5°-241.5° C.

EXAMPLE 81

6-[4-(3,4,5-Trimethoxycinnamoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless granular crystals

Melting point: 281°-284° C.

EXAMPLE 82

6-(4-Acetylmethyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 225°-227° C. (decomposed)

EXAMPLE 83

6-[4-(2-Hydroxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless flake-like crystals

Melting point: 156°-157.5° C.

EXAMPLE 84

6-[4-(2-Acetyloxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 239°-241° C. (decomposed)

EXAMPLE 85

6-{4-[3,4,5-Trimethoxybenzoyloxy)propyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 220°-222° C. (decomposed)

EXAMPLE 86

6-{4-[2-(3,4-Dimethoxybenzoyloxy)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride

Colorless rhombic crystals

Melting point: 240°-242° C. (decomposed)

EXAMPLE 87

6-(1-Piperazinylcarbonyl)carbostyril monohydrochloride

Colorless granular crystals

Melting point: over 300° C.

EXAMPLE 88

6-(4-Benzyl-1-piperazinylcarbonyl)carbostyril monohydrochloridemonohydrate

Colorless granular crystals

Melting point: over 300° C.

EXAMPLE 89

6-[4-(3-Chlorobenzoyl)-1-piperazinylcarbonyl]-carbostyril

Colorless powdery crystals

Melting point: over 300° C.

EXAMPLE 90

6-[4-(2-Phenoxyethyl)-1-piperazinylcarbonyl]carbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 286°-289° C. (decomposed)

EXAMPLE 91

6-[4-(3-Phenylpropyl)-1-piperazinylcarbonyl]carbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 290°-293° C. (decomposed)

EXAMPLE 92

6-[4-(4-Methylbenzyl)-1-piperazinylcarbonyl]-carbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: over 300° C.

EXAMPLE 93

6-(4-Isobutyl-1-piperazinylcarbonyl)carbostyril monohydrochloride1/2-hydrate

Colorless powdery crystals

Melting point: over 300° C.

EXAMPLE 94

6-[4-(3,4-Dichlorobenzyl)-1-piperazinylcarbonyl]-carbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: over 300° C.

EXAMPLE 95

6-[4-(4-Chlorobenzyl)-1-piperazinylcarbonyl]-carbostyrilmonohydrochloride

Colorless needle-like crystals

Melting point: over 300° C.

EXAMPLE 96

5-(4-Isobutyl-1-piperazinylcarbonyl)carbostyril monohydrochloride1/2-hydrate

Colorless powdery crystals

Melting point: 251°-254° C. (decomposed)

EXAMPLE 97

5-[4-(2-Phenoxyethyl)-1-piperazinylcarbonyl]-carbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 227°-229° C.

EXAMPLE 98

5-[4-(2-Benzoylethyl)-1-piperazinylcarbonyl]-carbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 181.5°-184° C.

EXAMPLE 99

5-[4-(3-Phenylpropyl)-1-piperazinylcarbonyl]-carbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 226°-228.5° C.

EXAMPLE 100

5-[4-(3,4-Methylenedioxybenzyl)-1-piperazinylcarbonyl]carbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 236°-239° C. (decomposed)

EXAMPLE 101

6-(2-Methyl-1-piperidylcarbonyl)-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 162°-164° C.

EXAMPLE 102

7-(4-Benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride

Colorless rhombic crystals

Melting point: 260°-262° C. (decomposed)

EXAMPLE 103

7-(4-Isobutyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless powdery crystals

Melting point: 262°-264° C. (decomposed)

EXAMPLE 104

7-[4-(2-Benzoylethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless rhombic crystals

Melting point: 205°-208° C. (decomposed)

EXAMPLE 105

7-[4-(2-Phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: 177°-180° C.

EXAMPLE 106

8-(4-Isobutyl-1-piperazinylcarbonyl)carbostyril monohydrochloride

Colorless powdery crystals

Melting point: 251°-254° C. (decomposed)

EXAMPLE 107

8-[4-(2-Benzoylethyl)-1-piperazinylcarbonyl]-carbostyril

Colorless powdery crystals

Melting point: 182°-184° C.

EXAMPLE 108

8-[4-(3-Phenylpropyl)-1-piperazinylcarbonyl]carbostyril

Colorless powdery crystals

Melting point: 195°-196° C.

EXAMPLE 109

0.64 Gram of β-chlorophenethol and 0.61 g of sodium iodide weresuspended in 7 ml of dimethylformamide and the mixture was stirred at aroom temperature for 30 minutes. Then to this mixture were added 1.0 gof 6-(1-piperazinylcarbonyl)carbostyril monohydrochloride and 1.2 g ofpotassium carbonate and the mixture was stirred at 70°-80° C. for 12hours. The reaction mixture was poured into 1 N-sodium hydroxide aqueoussolution and was extracted with chloroform. The chloroform layer waswashed with water and a saturated sodium chloride aqueous solution inthis order and dried with anhydrous sodium sulfate. After removal of thesolvent by distillation, the residue was dissolved in methanol and thepH was a adjusted to about pH 1 by adding concentrated hydrochloricacid. After removal of the solvent by distillation, the residue wasrecrystallized from ethanol-water to obtain 0.84 g of6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-carbostyrilmonohydrochloride. Colorless powdery crystals. Melting point: 286°-289°C. (decomposed)

EXAMPLE 110

3.0 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril, 2.9 g oftriethylamine, 2.7 g of β-chlorophenethol and 2.1 g of sodium iodidewere suspended in a mixed solvent of 20 ml of acetonitrile with 20 ml ofdimethylformamide, and the reaction mixture was refluxed for 15 hoursunder stirring condition. Then the solvents were removed bydistillation, and the residue thus obtained was extracted with a mixedsolvent of a saturated sodium bicarbonate aqueous solution withchloroform, the organic layer was washed with water and a saturatedsodium chloride aqueous solution in this order, then the extract wasdried with anhydrous sodium sulfate, and the solvent was removed bydistillation under a reduced pressure. To the thus obtained residue wasadded concentrated hydrochloric acid to adjust the pH of the residue toabout pH 1 so as to obtain the hydrochloride. Recrystallized fromethanol-water to obtain 2.13 g of6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride. Colorless needle-like crystals. Melting point:271°-274° C. (decomposed)

By methods similar to those described in Examples 109 and 110 and usingsuitable starting materials, there were obtained compounds of Examples8, 24, 25, 36, 37, 44, 45, 46, 51, 52, 58-79, 82-86, 90, 91, 93, 96-99,103-108.

EXAMPLE 111

1.0 Gram of 6-(1-piperazinylcarbonyl)carbostyrilmonohydrochloride, 0.7 gof p-chlorobenzylchloride and 1.4 ml of triethylamine were suspended in15 ml of acetonitrile and stirred at 50°-70° C. for 4 hours. Then thereaction was continued on an ice bath for 1 hour so as to form crystalsin the reaction mixture. Thus formed crystals were collected byfiltration and extracted with chloroform-saturated sodium bicarbonateaqueous solution, the chloroform layer was washed with water and asaturated sodium chloride aqueous solution in this order and dried withanhydrous sodium sulfate. The solvent was removed by distillation undera reduced pressure and the residue thus obtained was dissolved inmethanol and the pH of the methanol solution was adjusted to about pH 1by adding concentrated hydrochloric acid. Crude crystals wererecrystallized from ethanol-water to obtain 0.73 g of6-[4-(4-chlorobenzyl)-1-piperazinyl-carbonyl]carbostyrilmonohydrochloride. Colorless needle-like crystals. Melting point: over300° C.

EXAMPLE 112

2.6 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril, 3.0 g oftriethylamine and 2.9 g of 3,4-dimethoxybenzylchloride were suspended inacetonitrile and the suspension was stirred at 50°-55° C. for 2 hours.After removal of the solvent the residue thus obtained was extractedwith chloroform, and the chloroform extract was washed with water and asaturated sodium chloride aqueous solution in this order, dried withanhydrous sodium sulfate. The solvent was removed by distillation andthe pH of thus obtained residue was adjusted by adding concentratedhydrochloric acid to about pH 1 so as to form the hydrochloride of theproduct. Recrystallized from methanol-water to obtain 1.50 g of6-[4-(3,4-dimethoxybenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride. Colorless granular crystals. Melting point: 240°-242°C. (decomposed)

By methods similar to those described in Examples 111 and 112 and usingsuitable starting materials, there were obtained compounds of Examples6, 11-15, 25, 26, 30-41, 43-46, 49, 53, 88, 91, 92, 94, 95, 99, 100, 102and 108.

EXAMPLE 113

1.0 Gram of 6-(1-piperazinylcarbonyl)carbostyril monohydrochloride, 0.72g of m-chlorobenzoylchloride and 1.4 ml of triethylamine were suspendedin 15 ml of dichloromethane and the suspension was stirred at a roomtemperature for 2 hours. Crystals formed in the reaction mixture werecollected by filtration and recrystallized from dimethylformamide toobtain 1.07 g of6-[4-(3-chlorobenzoyl)-1-piperazinylcarbonyl]-carbostyril. Colorlesspowdery crystals. Melting point: over 300° C.

EXAMPLE 114

3.0 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril and 4.0 mlof tiethylamine were suspended in 20 ml of dichloromethane, and to thesuspension was added dropwise 3.5 g of 3,4-dimethoxybenzoylchloride in20 ml of dichloromethane under ice-cooled condition with stirring. Thenthe reaction was continued for additional 1 hour at a room temperature.The reaction mixture was poured into a saturated sodium bicarbonateaqueous solution and extracted with chloroform. The chloroform layer waswashed with water and a saturated sodium chloride aqueous solution inthis order and was dired with anhydrous sodium sulfate, and the solventwas removed by distillation. The residue thus obtained wasrecrystallized from ethanol-chloroform to obtain 4.1 g of6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.Colorless granular crystals. Melting point: 238°-239.5° C.

By methods similar to those described in Examples 113 and 114 and usingsuitable starting materials, there were obtained compounds of Examples17-23, 29, 42, 47, 48, 50, 80, 81 and 89.

EXAMPLE 115

1.5 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril and 1.5 gof triethylamine were suspended in 10 ml of dichloromethane. Underice-cooled and stirring condition, 1.4 g of p-toluenesulfonylchloride in10 ml of dichloromethane solution was added dropwise to the suspensionand the reaction was continued for additionally 3 hours at a roomtemperature, further continued for 1 hour under ice-cooled condition.The crystals formed in the reaction mixture were collected by filtrationand recrystallized from chloroform-ether to obtain 1.4 g of6-[4-(p-toluenesulfonyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.Colorless granular crystals. Melting point: 280°-282° C.

By a method similar to that described in Exmple 115 and using a suitablestarting material, there was obtained a compound of Example 28.

EXAMPLE 116

2.62 Grams of 6-morpholinocarbonyl-3,4-dihydrocarbostyril and 17.9 g of3,4-dimethoxybenzylamine were placed in a sealed tube and heated at170°-200° C. for 5 hours. Then 3,4-dimethoxybenzylamine was removed bydistillation under a reduced pressure and the residue thus obtained wastreated by means of a silica gel column chromatography, and theobjective product was changed to a hydrochloride by adding concentratedhydrochloric acid. Recrystallized from methanol-water to obtain 0.35 gof6-[4-(3,4-dimethoxybenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride. Colorless granular crystals. Melting point: 240°-242°C. (decomposed)

By a method similar to that described in Example 116, and using asuitable starting material there were obtained compounds of Examples of6-8, 11-15, 24, 25, 26, 30-41, 43-46, 49, 51-53, 58-79, 82-86 and90-108.

EXAMPLE 117

A mixture of 10 g of6-[bis-(2-hydroxyethyl)-aminocarbonyl]-3,4-dihydrocarbostyril, 4.5 g of3,4-dimethoxybenzylamine and 7.6 g of a polyphosphoric acid was heatedat 160°-170° C. for about 6 hours to be reacted. After the reaction wascompleted, the reaction mixture was allowed to cooled and 500 ml ofwater was added thereto to dissolve. The solution was neutralized with48% of sodium hydroxide solution and extracted with chloroform. Thechloroform extract was dried with anhydrous potassium carbonate, thechloroform was removed by distillation, then to the residue thusobtained was added concentrated hydrochloric acid so as to form theobjective product into the hydrochloride. Recrystallized frommethanol-water to obtain 7.5 g of6-[4-(3,4-dimethoxybenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride. Colorless granular crystals. Melting point: 240°-242°C. (decomposed)

By a method similar to that described in Example 117 and using suitablestarting materials, there were obtained compounds of Examples 1-8,11-15, 24-26, 30-41, 43-46, 49, 51-53, 58-79, 82-86 and 90-108.

EXAMPLE 118

A mixture of 15.9 g of6-[bis-(2-chloroethyl)-aminocarbonyl]-3,4-dihydrocarbostyril, 9.8 g of3,4-dimethoxybenzylamine and 70 ml of methanol was refluxed withstirring for 15 hours. After the reaction was completed, the reactionmixture was cooled, then 3.06 g of sodium carbonate was added to themixture and refluxed with stirring for 8 hours. After cooling themixture, crystals formed were collected by filtration, and thehydrochloride was formed by adding concentrated hydrochloric acid.Recrystallized from methanol-water to obtain 7.3 g of6-[4-(3,4-dimethoxybenzyl)-1-piperazinyl-carbonyl]-3,4-dihydrocarbostyrilmonohydrochloride. Colorless granular crystals. Melting point: 240°-242°C. (decomposed)

By a method similar to that described in Example 118, and using asuitable starting material, there were obtained compounds of Examples1-8, 11-15, 24-26, 30-41, 43-46, 49, 51-53, 58-79, 82-86 and 90-108.

EXAMPLE 119

1.0 Gram of 6-carboxy-3,4-dihydrocarbostyril, 1.3 g of DCC and 1.1 g ofbenzylpiperazine were suspended in 10 ml of dioxane and the suspensionwas stirred at 70° C. for 5 hours. After the reaction was completed, thesolvent was removed by distillation and ether was added to the residueand crystals formed were removed by filtration. After the mother liquorwas concentrated, the residue was dissolved in chloroform and thechloroform solution was washed with water and a saturated sodiumchloride aqueous solution then dried with anhydrous sodium sulfate andthe solvent was removed by distillation. Recrystallized from ethanol toobtain 330 mg of6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorlessneedle-like crystals. Melting point: 198°-200° C.

By a method similar to that described in Example 119, and using asuitable starting material, there were obtained compounds of Examples 1,2, 3, 4, 5 and 7-108.

EXAMPLE 120

1.0 Gram of 6-carboxy-3,4-dihydrocarbostyril and 0.8 ml of triethylaminewere suspended in 10 ml of tetrahydrofuran, and under stirring at a roomtemperature condition, 1.0 g of diethylchlorophosphate in 10 ml oftetrahydrofuran solution was added dropwise to the suspension, andstirred at a room temperature for 3 hours. To this reaction mixture, 1.1g of benzylpiperazine in 10 ml of tetrahydrofuran solution was addeddropwise then stirred at a room temperature for 10 hours. After thereaction was completed, the crystals formed in the reaction mixture wereremoved by filtration and the mother liquor was concentrated, and to theresidue thus obtained was poured a saturated sodium bicarbonate aqueoussolution and then extracted with chloroform. The organic layer waswashed with water and a saturated sodium chloride aqueous solution thendried with anhydrous sodium sulfate and the solvent was removed bydistillation. Recrystallized from ethanol 1.07 g of6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorlessneedle-like crystals. Melting point: 198°-200° C.

By a method similar to that described in Example 120, and using asuitable starting material, there were obtained compounds of Examples 1,2, 3, 4, 5, 7-108.

EXAMPLE 121

34.5 Grams of 6-carboxycarbostyril and 31 ml of triethylamine weredissolved in 350 ml of dimethylformamide and stirred at a roomtemperature. Then 28 ml of isobutyl chloroformate in 14 ml ofdimethylformamide solution was added dropwise to the former solution.After stirring at a room temperature for 1 hour, 37 g ofbenzylpiperazine in 21 ml of dimethylformamide solution was addeddropwise to the reaction mixture and stirred at a room temperature for10 hours. The reaction mixture was poured into a saturated sodiumbicarbonate aqueous solution, then extracted with chloroform. Thechloroform layer was washed with water and a saturated sodium chlorideaqueous solution in this order and the chloroform extract was dried withanhydrous sodium sulfate. The solvent was removed by distillation undera reduced pressure, the residue thus obtained was crystallized by addingether and the crystals were collected by filtration. The crystals weredissolved in methanol and the pH of the solution was adjusted to aboutpH 1 by adding concentrated hydrochloric acid. The crude crystals thusobtained were recrystallized from ethanol-water to obtain 30.1 g of6-(4-benzyl-1-piperazinylcarbonyl)carbostyril monohydrochloridemonohydrate. Colorless granular crystals. Melting point: over 300° C.

EXAMPLE 122

To a solution of 50 ml of dimethylformamide with 5.0 g of6-carboxy-3,4-dihydrocarbostyril and 4 ml of triethylamine, 3.87 g ofisobutyl chloroformate in 2 ml of dimethylformamide solution was addeddropwise. After stirring at a room temperature for 30 minutes, 5.5 g ofbenzylpiperazine in 3 ml of dimethylformamide solution was added to theformer solution and stirred at a room temperature for 30 minutes, thenstirred continuously at 50°-60° C. for 1 hour. The reaction mixture waspoured into a voluminous amount of a saturated sodium chloride aqueoussolution and extracted with chloroform and the chloroform extract waswashed with water and dried. After removal of the solvent, to theresidue thus obtained was added diethyl ether to crystallize the residueand recrystallized from ethanol to obtain 3.4 g of6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorlessneedle-like crystals. Melting point: 198°-200° C.

By methods similar to those described in Examples 121 and 122 by using asuitable starting material, there were obtained compounds of Examples 3,4, 5, 7-87 and 89-108.

EXAMPLE 123

To 100 ml of ethanol was added 2.0 g of6-ethoxycarbonyl-3,4-dihydrocarbostyril, 0.5 g of sodium ethylate and1.6 g of benzylpiperazine, the mixture was reacted in an autoclave under110 atmospheric pressure at 140°-150° C. for 6 hours. After the reactionwas completed, the reaction mixture was cooled and concentrated under areduced pressure. The residue thus obtained was dissolved in 200 ml ofchloroform and the chloroform solution was washed with 1%-potassiumcarbonate aqueous solution, a diluted hydrochloric acid and water inthis order, then dried with anhydrous sodium sulfate. The solvent wasremoved by distillation and the residue was treated by means of a silicagel column chromatography (Silica gel: Wako C-200, eluate:chloroform:methanol (volume/volume)=20:1) and the crude crystals wererecrystallized from ethanol to obtain 300 mg of6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihyrocarbostyril. Colorlessneedle-like crystals. Melting point: 198°-200° C.

By a method similar to that described in Example 123 by using a suitablestarting material, there were obtained compounds of Examples 1-5, 7-108.

EXAMPLE 124

1.9 Grams of 6-carboxy-3,4-dihydrocarbostyril was suspended in 200 ml ofmethylene chloride, then 2 ml of pyridine was added to the suspensionand under stirring 1.4 g of thionyl chloride was added dropwise inkeeping the inside temperature at 0°-20° C. After the addition ofthionyl chloride, the reaction mixture was kept at the same temperatureand stirred for 1 hour, then 1.74 g of benzylpiperazine in 10 ml ofmethylene chloride solution was added to the mixture. Then the reactionmixture was further stirred at a room temperature for 4 hours. Thereaction mixture was washed thoroughly with an aqueous solution ofpotassium carbonate, then washed with water and a diluted hydrochloricacid, dried with anhydrous sodium sulfate and the solvent was removed bydistillation. The residue thus obtained was treated by a silica gelcolumn chromatography (Silica gel: Wako C-200, eluate:chloroform:methanol (volume/volume)=20:1). The objective product wasrecrystallized from ethanol to obtain 325 mg of6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorlessneedle-like crystals. Melting point: 198°-200° C.

By a method similar to that described in Example 124 and using asuitable starting material, there were obtained compounds of Examples1-5 and 7-108.

EXAMPLE 125

Into 100 ml of dimethylformamide, 2.6 g of 3,4-dimethoxybenzoic acid and1.65 g of 1,8-diazabicyclo[5,4,0]undecene-7 were added, then the outsideof the reaction vessel was ice-cooled and stirring condition, 1.5 ml ofisobutyl chloroformate was added dropwise. Then the reaction mixture wasfurther stirred for 30 minutes, a solution of 2.6 g of6-(1-piperazinyl)-carbonyl-3,4-dihydrocarbostyril dissolved in 40 ml ofdimethylformamide was added to the reaction mixture and stirred at aroom temperature for 5 hours. After the reaction was completed, thesolvent was removed by distillation and the residue was extracted withabout 300 ml of chloroform, then washed with a diluted sodiumhydrogencarbonate aqueous solution, water, a diluted hydrochloric acidand water in this order. After removal of chloroform by distillation,the residue was recrystallized from ethanol-chloroform to obtain 1.8 gof6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.Colorless granular crystals. Melting point: 238°-239.5° C.

By a method similar to that described in Example 125 and using asuitable starting material, there were obtained compounds of Examples17-23, 29, 42, 47, 48, 50, 80, 81 and 89.

EXAMPLE 126

123 Grams of succinimide 3,4-dimethoxybenzoate and 137 mg of6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril were dissolved in 2 mlof dimethylformamide and stirred for 24 hours. The water was added tothe reaction mixture and extracted with chloroform, the chloroformextract was washed with water and a saturated sodium chloride aqueoussolution and dried with anhydrous sodium sulfate. The solvent wasremoved by distillation and the residue was recrystallized fromethanol-chloroform to obtain 100 mg of6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.Colorless granular crystals. Melting point: 238°-239.5° C.

By a method similar to that described in Example 126 and using asuitable starting material, there were obtained compounds of Examples17-23, 29, 42, 47, 48, 50, 80, 81 and 89.

EXAMPLE 127

To a solution of 4.8 g of 3,4-dimethoxybenzoic acid and 4 ml oftriethylamine in 50 ml of dimethylformamide, a solution of 3.87 g ofisobutylchloroformate in 2 ml of dimethylformamide was added dropwise.After the reaction mixture was stirred at a room temperature for 30minutes, then a solution of 8.1 g of6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril in 3 ml ofdimethylformamide was added dropwise to the reaction mixture and stirredat a room temperature for 30 minutes, and further stirred at 50°-60° C.for 1 hour. After the reaction was completed, the reaction mixture waspoured into a voluminous amount of a saturated sodium chloride aqueoussolution and then extracted with chloroform and the chloroform extractwas washed with water and dried. The solvent was removed bydistillation, and the residue was recrystallized from ethanol-chloroformto obtain 2.5 g of6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.Colorless granular crystals. Melting point: 238°-239.5° C.

By a method similar to that described in Example 127 and using asuitable starting material, there were obtained compounds of Examples17-23, 29, 42, 47, 48, 50, 80, 81 and 89.

EXAMPLE 128

To 100 ml of ethanol was added 1.9 g of ethyl 3,4-dimethoxybenzoate, 0.5g sodium ethylate and 2.4 g of6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril, the mixture wasreacted in an autoclave under 110 atmospheric pressure at 140°-150° C.for 6 hours. After the reaction was completed, the reaction mixture wascooled and concentrated under a reduced pressure. The residue thusobtained was dissolved in 200 ml of chloroform and the chloroformsolution was washed with 1%-potassium carbonate aqueous solution, adilute hydrochloric acid and water in this order, then dried withanhydrous sodium sulfate. The solvent was removed by distillation andthe residue was treated by means of a silica gel column chromatography(Silica gel: Wako C-200, eluent: chloroform:methanol(volume/volume)=20:1) and the crude crystals were recrystallized fromethanol-chloroform to obtain 250 mg of6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.Colorless granular crystals. Melting point: 238°-239.5° C.

By a method similar to that described in Example 128 and using asuitable starting material, there were obtained compounds of Examples17-23, 29, 42, 47, 48, 50, 80, 81 and 89.

EXAMPLE 129

1.8 Grams of 3,4-dimethoxybenzoic acid and 2.75 g of6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril were added to a mixedsolvent of 20 ml of dioxane with 20 ml of methylene chloride. Under thecondition that the outside of reaction vessel was ince-cooled withstirring, a solution of 2.1 g of N,N-dicyclohexylcarbodiimide beingdissolved in 5 ml of methylene chloride by keeping its temperature to10°-20° C. was added dropwise thereto and stirred at the sametemperature for 3.5 hours. The crystals formed in the reaction mixturewas removed by filtration, and the mother liquor was concentrated undera reduced pressure. The residue thus obtained was dissolved in 100 ml ofmethylene chloride and the organic layer was washed with 5%-hydrochloricacid aqueous solution, 5%-sodium hydrogencarbonate aqueous solution andwater in this order, then the organic layer was dried with anhydroussodium sulfate. The solvent was removed by distillation under a reducedpressure and the residue thus obtained was recrystallized fromchloroform-ethanol to obtain 0.9 g of6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbony]-3,4-dihydrocarbostyril.Colorless granular crystals. Melting point: 238°-239.5° C.

By a method similar to that described in Example 129 and using asuitable starting material, there were obtained compounds of Examples17-23, 29, 42, 47, 48, 50, 80, 81 and 89.

EXAMPLE 130

480 Milligrams of6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and70 ml of 50%-sodium hydride in oil were mixed into 5 ml ofdimethylformamide and stirred at a room temperature for 1 hour. Then tothis mixture was added a solution of 0.17 ml of benzyl chloride with 3ml of dimethylformamide was added dropwise slowly and stirred at a roomtemperature for 4 hours. The reaction mixture was poured in a voluminousamount of water and the organic matters were extracted with chloroform,and the chloroform layer was washed with water, dried and chloroform wasremoved by distillation. The residue obtained was converted intohydrochloride by adding a concentrated hydrochloric acid andrecrystallized from methanol-water to obtain 150 mg of1-benzyl-6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride. Colorless powdery crystals. Melting point: 261°-264°C.

By a method similar to that described in Example 130 and using asuitable starting material, there were obtained compounds of Examples43, 44 and 46.

EXAMPLE 131

26.4 Grams of 6-[(4-benzyl-1-piperazinyl)carbonyl]carbostyril wassuspended in 800 ml of a mixed solvent of ethanol-water and the pH ofthe suspension was adjusted to about pH 1 by adding concentratedhydrochloric acid. To this mixture was added 2.6 g of 5%palladium-carbon and catalytic reduction was conducted under a normalpressure at 45°-65° C. After the reaction was completed, the catalystwas removed by filtration and the solvent was removed by distillationunder a reduced pressure. The residue obtained was crystallized byadding acetone and the crude crystals thus obtained were recrystallizedfrom ethanol-water to obtain 19.9 g of6-(1-piperazinylcarbonyl)carbostyril monohydrochloride. Colorlessgranular crystals. Melting point: over 300° C.

EXAMPLE 132

By method similar to those described in Examples 6, 110, 112, 116, 117,118, 119, 120, 122, 123 and 124 and using a suitable starting material,there were obtained compounds as follows:

6-{4-[2-(3,4,5-Trimethoxyphenoxy)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyrilmonohydrochloride 1/2 hydrate

Colorless powdery crystals

Melting point: 238.5°-240° C.

6-[4-(2-Chloropropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 238°-239° C. (decomposed)

6-(4-Ethoxycarbonylmethyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 232°-234° C. (decomposed)

6-[4-(2-Ethoxycarbonylethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride

Colorless powdery crystals

Melting point: 227°-229.5° C. (decomposed)

6-(4-Propyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride 1/2-hydrate

Colorless flake-like crystals

Melting point: 259°-262° C.

6-(4-Isopentyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride

Colorless flake-like crystals

Melting point: over 300° C.

8-(4-Benzyl-1-piperazinylcarbonyl)carbostyril monohydrochloride3/2-hydrate

Colorless powdery crystals

Melting point: 177°-180° C.

5-(4-Benzyl-1-piperazinylcarbonyl)carbostyril monohydrochloridemonohydrate

Colorless granular crystals

Melting point: 204°-207° C.

EXAMPLE 133

1.2 Grams of acetic anhydride and 0.6 g of formic acid were stirred at60° C. for 2 hours, then 1.0 g of 6-(1-piperazinylcarbonyl)carbostyrilwas added thereto and the mixture was stirred at a room temperature for1 hour. After the reaction was completed, the reaction mixture waspoured into water and neutrallized with 1 N-sodium hydroxide aqueoussolution, then extracted with chloroform. The organic layer was washedwith water and a saturated sodium chloride aqueous solution in thisorder, the organic layer was dried with anhydrous sodium sulfate and thesolvent was removed by distillation under a reduced pressure. Theresidue obtained was crystallized by adding ether and the crude crystalsobtained were recrystallized from ethanol to obtain 0.15 g of6-(4-formly-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorlesspowdery crystals.

Melting point: 198°-201° C.

EXAMPLE 134

0.5 Gram of6-[4-(2-hydroxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and0.3 ml of triethylamine were dissolved in 10 ml of dichloromethane, themixture was stirred at a room temperature, 0.15 g of acetyl chloride wasadded slowly thereto and further stirred at a room temperature for 1hour. The reaction mixture was poured into a saturated sodiumbicarbonate aqueous solution and extracted with chloroform. The organiclayer was washed with water and a saturated sodium chloride aqueoussolution and extracted with chloroform. The organic layer was washedwith water and a saturated sodium chloride aqueous solution then driedwith anhydrous sodium sulfate. The solvent was removed by distillationunder a reduced pressure and the residue obtained was treated by meansof a silica gel column chromatography, then the objective product wasdissolved in methanol and converted into the hydrochloride by adding aconcentrated hydrochloric acid. Recrystallized from water-acetone toobtain 0.22 g of6-[4-(2-acetoxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrilmonohydrochloride. Melting point: 239°-241° C. (decomposed)

EXAMPLE 135

3.76 Grams of6-(4-acetylmethyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyrilmonohydrochloride was dissolved in 50 ml of methanol, under ice-cooledcondition, 0.44 g of sodium borohydride (NaBH₄) was added slowly andthen stirred at a room temperature for 1 hour. After the reaction wascompleted, a concentrated hydrochloric acid was added to adjust the pHof the reaction mixture to about pH 1, then most portion of the solventwas removed by distillation under a reduced pressure and the residue wasextracted with 1 N-NaOH-chloroform. The organic layer was washed withwater and dried with anhydrous sodium sulfate, then the solvent wasremoved by distillation. The residue obtained was treated by means of acolumn chromatography and recrystallized from ethanol to obtain 2.26 gof 6-[4-(2-hydroxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.Colorless flake-like crystals. Melting point: 156°-157.5° C.

EXAMPLE 136

By a method similar to that described in Examples 6, 114, 119, 120, 122,123, 124, 125, 126, 127, 128 and 129 and using a suitable startingmaterial, there is obtained compound as follows:

6-[4-(4-Methoxyphenyl)acetyl-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril

Colorless powdery crystals

Melting point: 158°-160° C.

EXAMPLE 137

By a method similar to that described in Examples 119, 120, 122-124 and131, and using a follows:

5-(1-Piperazinylcarbonyl)carbostyril monohydrochloride 1/2-hydrate

Colorless granular crystals

Melting point: over 300° C.

7-(1-Piperazinylcarbonyl)-3,4-dihydrocarbostyril monohydrochloride

Colorless granular crystals

Melting point: 261.5°-263° C.

8-(1-Piperazinylcarbonyl)carbostyril

Colorless granular crystals

Melting point: over 300° C.

What is claimed is:
 1. A carbostyril derivative or a pharmaceuticallyacceptable salt thereof) said derivative being represented by theformula (1), ##STR30## wherein R¹ is a hydrogen atom, a lower alkylgroup, a lower alkenyl group, a lower alkynyl group or a phenyl-loweralkyl group, R² and R³ form, together with the adjacent nitrogen atomand further with an additional oxygen atom, a 5- or 6-membered saturatedheterocyclic ring which may have a lower alkyl group or a phenyl-loweralkyl group as the substituent; the carbon-carbon bond between 3- and4-positions in the carbostyril skeleton being a single or double bond.2. A cardiotonic composition containing an effective amount of acarbostyril derivative of claim 1 or one of its pharmaceuticallyacceptable salts as the active ingredient.